Method of inhibiting c-kit kinase

ABSTRACT

A method of reducing or inhibiting kinase activity of C-KIT in a cell or a subject, and the use of such compounds for preventing or treating in a subject a cell proliferative disorder and/or disorders related to C-KIT using a compound of the present invention: 
     
       
         
         
             
             
         
       
     
     or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. 
     The present invention is further directed to methods for treating conditions such as cancers and other cell proliferative disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application PatentNo. 60/793,471, filed Apr. 20, 2006, the entire disclosure of which ishereby incorporated in its entirely.

FIELD OF THE INVENTION

The present invention relates to methods of reducing or inhibitingkinase activity of C-KIT in a cell or a subject, and the use of suchmethods for preventing or treating in a subject a cell proliferativedisorder and/or disorders related to C-KIT.

BACKGROUND OF THE INVENTION

Protein kinases are enzymatic components of the signal transductionpathways which catalyze the transfer of the terminal phosphate from ATPto the hydroxy group of tyrosine, serine and/or threonine residues ofproteins. Thus, compounds which inhibit protein kinase functions arevaluable tools for assessing the physiological consequences of proteinkinase activation. The overexpression or inappropriate expression ofnormal or mutant protein kinases in mammals has been a topic ofextensive study and has been demonstrated to play a significant role inthe development of many diseases, including diabetes, angiogenesis,psoriasis, restenosis, ocular diseases, schizophrenia, rheumatoidarthritis, atherosclerosis, cardiovascular disease and cancer. Thecardiotonic benefits of kinase inhibition has also been studied. In sum,inhibitors of protein kinases have particular utility in the treatmentof human and animal disease.

The receptor tyrosine kinase C-KIT and its ligand Stem Cell Factor (SCF)are essential for hemoatpoiesis, melanogenesis and fertility. SCF actsat multiple levels of the hemoatpoietic hierarchy to promote cellsurvival, proliferation, differentiation, adhesion and functionalactivation. It is of particular importance in the mast cell anderythroid lineages, but also acts on multipotential stem and progenitorcells, megakaryocytes, and a subset of lymphoid progenitors (see, Int JBiochem Cell Biol. 1999 October; 31(10):1037-51). Sporadic mutations ofC-KIT as well as autocrine/paracrine activation mechanisms of theSCF/C-KIT pathway have been implicated in a variety of malignancies.Activation of C-KIT contributes to metastases by enhancing tumor growthand reducing apoptosis. Additionally, C-KIT is frequently mutated andactivated in gastrointestinal stromal tumors (GISTs), andligand-mediated activation of C-KIT is present in some lung cancers(see, Leuk Res. 2004 May; 28 Suppl 1:S11-20). The C-KIT receptor also isexpressed on more than 10% of blasts in 64% of de novo acute myelogenousleukemias (AMLs) and 95% of relapsed AMLs. C-kit mediates proliferationand anti-apoptotic effects in AML (see, Curr Hematol Rep. 2005 January;4(1):51-8).

C-Kit expression has been documented in a wide variety of humanmalignancies, including mastocytosis, mast cell leukemia,gastrointestinal stromal tumour, sinonasal natural killer/T-celllymphoma, seminoma, dysgerminoma, thyroid carcinoma; small-cell lungcarcinoma, malignant melanoma, adenoid cystic carcinoma, ovariancarcinoma, acute myelogenous leukemia, anaplastic large cell lymphoma,angiosarcoma, endometrial carcinoma, pediatric T-cell ALL, lymphoma,breast carcinoma and prostate carcinoma. See, Heinrich, Michael C. etal. Review Article: Inhibition of KIT Tyrosine Kinase Activity: A NovelMolecular Approach to the Treatment of KIT-Positive Malignancies.Journal of Clinical Oncology, Vol 20, No 6 (March 15), 2002: pp1692-1703.

SUMMARY OF THE INVENTION

The present invention provides methods of reducing or inhibiting kinaseactivity of C-KIT in a cell or a subject, and the use of such methodsfor preventing or treating in a subject a cell proliferative disorderand/or disorders related to C-KIT.

Other features and advantages of the invention will be apparent from thefollowing detailed description of the invention and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The terms “comprising”, “including”, and “containing” are used herein intheir open, non-limited sense.

Abbreviations

As used herein, the following abbreviations are intended to have thefollowing meanings (additional abbreviations are provided where neededthroughout the Specification):

-   ATP adenosine triphosphate-   Boc or BOC tert-butoxycarbonyl-   DCM dichloromethane-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   DIEA diisopropylethylamine-   EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraaceticacid-   EtOAc ethyl acetate-   FP fluorescence polarization-   HOBT or HOBt 1-hydroxybenzotriazole hydrate-   LC/MS (ESI) Liquid chromatography/mass spectrum (electrospray    ionization)-   MeOH Methyl alcohol-   NMR nuclear magnetic resonance-   RT room temperature-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography

DEFINITIONS

The term “alkyl” refers to both linear and branched chain radicals of upto 12 carbon atoms, preferably up to 6 carbon atoms, unless otherwiseindicated, and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, isohexyl, heptyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl,undecyl and dodecyl.

The term “hydroxyalkyl” refers to both linear and branched chainradicals of up to 6 carbon atoms, in which one hydrogen atom has beenreplaced with an OH group.

The term “hydroxyalkylamino” refers to an hydroxyalkyl group in whichone hydrogen atom from the carbon chain has been replaced with an aminogroup, wherein the nitrogen is the point of attachment to the rest ofthe molecule.

The term “cycloalkyl” refers to a saturated or partially unsaturatedring composed of from 3 to 8 carbon atoms. Up to four alkyl substituentsmay optionally be present on the ring. Examples include cyclopropyl,1,1-dimethyl cyclobutyl, 1,2,3-trimethylcyclopentyl, cyclohexyl,cyclopentenyl, cyclohexenyl, and 4,4-dimethyl cyclohexenyl.

The term “dihydrosulfonopyranyl” refers to the following radical:

The term “hydroxyalkyl” refers to at least one hydroxyl group bonded toany carbon atom along an alkyl chain.

The term “aminoalkyl” refers to at least one primary or secondary aminogroup bonded to any carbon atom along an alkyl chain, wherein an alkylgroup is the point of attachment to the rest of the molecule.

The term “alkylamino” refers to an amino with one alkyl substituent,wherein the amino group is the point of attachment to the rest of themolecule.

The term “dialkylamino” refers to an amino with two alkyl substituents,wherein the amino group is the point of attachment to the rest of themolecule.

The term “heteroaromatic” or “heteroaryl” refers to 5- to 7-memberedmono- or 8- to 10-membered bicyclic aromatic ring systems, any ring ofwhich may consist of from one to four heteroatoms selected from N, O orS where the nitrogen and sulfur atoms can exist in any allowed oxidationstate. Examples include benzimidazolyl, benzothiazolyl, benzothienyl,benzoxazolyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl,pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl,thiazolyl and thienyl.

The term “heteroatom” refers to a nitrogen atom, an oxygen atom or asulfur atom wherein the nitrogen and sulfur atoms can exist in anyallowed oxidation states.

The term “alkoxy” refers to straight or branched chain radicals of up to12 carbon atoms, unless otherwise indicated, bonded to an oxygen atom.Examples include methoxy, ethoxy, propoxy, isopropoxy and butoxy.

The term “aryl” refers to monocyclic or bicyclic aromatic ring systemscontaining from 6 to 12 carbons in the ring. Alkyl substituents mayoptionally be present on the ring. Examples include benzene, biphenyland napththalene.

The term “aralkyl” refers to a C₁₋₆ alkyl group containing an arylsubstituent. Examples include benzyl, phenylethyl or 2-naphthylmethyl.

The term “sulfonyl” refers to the group —S(O)₂R_(a), where R_(a) ishydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl. A “sulfonylating agent” adds the —S(O)₂R_(a) group to amolecule.

Formula I

The present invention comprises methods of using the compounds ofFormula I (referred to herein as “the compounds of the presentinvention”):

or a solvate, hydrate, tautomer or pharmaceutically acceptable saltthereof, wherein:

A is

-   -   phenyl or pyridyl, either of which may be substituted with one        of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂,        —S(alkyl), —O(alkyl), or 4-aminophenyl;

W is

-   -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —Cl, —CN, —NO₂, —OMe, or —CF₃ substitution, connected to any        other carbon;

R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl,        dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or        dihydropyranyl, any of which may be independently substituted        with one or two of each of the following: chloro, fluoro, and        C₍₁₋₃₎alkyl (including 4,4-dimethyl cyclohexenyl, 4-methyl        cyclohexenyl, 2-methyl thiophenyl, 3-methyl thiophenyl), with        the proviso that tetrahydropyridyl is connected to the ring A        through a carbon-carbon bond;

X is

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂-amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from 5, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

EMBODIMENTS

Embodiments of the present invention include a compound of Formula Iwherein:

a) A is

-   -   phenyl or pyridyl, either of which may be substituted with one        of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂,        —S(alkyl), —O(alkyl), or 4-aminophenyl;

b) A is

-   -   phenyl;

c) W is

-   -   pyrrolyl (including 1H-pyrrol-2-yl), imidazolyl, (including        1H-imidazol-2-yl), isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl (including furan-2-yl), any of which may be connected        through any carbon atom, wherein the pyrrolyl, imidazolyl,        isoxazolyl, oxazolyl, 1,2,4 triazolyl, or furanyl may contain        one —Cl, —CN, —NO₂, —OMe, or —CF₃ substitution, connected to any        other carbon;

d) W is

-   -   furan-2-yl, 1H-pyrrol-2-yl, or 1H-imidazol-2-yl, any of which        may be substituted at the 4 or 5 carbons with —CN;

e) W is

-   -   3H-2-imidazolyl-4-carbonitrile or 5-cyano-1H-pyrrol-2-yl;

f) W is

-   -   3H-2-imidazolyl-4-carbonitrile;

g) R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), thiophenyl,        dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl, or        dihydropyranyl, any of which may be independently substituted        with one or two of each of the following: chloro, fluoro, and        C₍₁₋₃₎alkyl (including 4,4-dimethyl cyclohexenyl, 4-methyl        cyclohexenyl, 2-methyl thiophenyl, 3-methyl thiophenyl), with        the proviso that tetrahydropyridyl is connected to the ring A        through a carbon-carbon bond;

h) R² is

-   -   cycloalkyl (including cyclohexenyl, cyclopentenyl), which may        substituted with one or two C₍₁₋₃₎alkyl (including 4,4-dimethyl        cyclohexenyl, 4-methyl cyclohexenyl);

i) R² is

-   -   cyclohexenyl, which may substituted with one or two C₍₁₋₃₎alkyl:

j) R² is

-   -   cyclohexenyl, 4,4-dimethyl cyclohexenyl, or 4-methyl        cyclohexenyl;

k) R² is

-   -   cyclohexenyl;

l) X is

m) X is

n) X is

o) Z is

-   -   CH or N;

p) Z is

-   -   CH;

q) D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

r) D¹ and D² are

-   -   each hydrogen;

s) D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

t) D³ and D⁴ are

-   -   each hydrogen;

u) D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        v) R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

w) E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

x) E is

-   -   N, with the proviso that E may not be N if the following three        conditions are simultaneously met: Q_(a) is absent, Q_(b) is        absent, and R³ is an amino group or cyclic amino radical wherein        the point of attachment to E is N;

y) Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

z) Q_(a) is

-   -   absent, —CH₂CH₂—, or C(O);

aa) Q_(a) is

-   -   absent, or C(O);

bb) Q_(a) is

-   -   C(O);

CC) Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

dd) Q_(b) is

-   -   absent, —CH₂CH₂—, or C(O), with the proviso that Q_(b) may not        be C(O) if Q_(a) is C(O);

ee) Q_(b) is

-   -   absent, or C(O), with the proviso that Q_(b) may not be C(O) if        Q_(a) is C(O);

ff) R³ is

-   -   hydrogen, phenyl, hydroxyalkylamino (including 2-hydroxy        ethylamino), (hydroxyalkyl)₂-amino, hydroxyalkyl(alkyl)amino        (including 1-hydroxyeth-2-yl(methyl)amino), alkylamino        (including methylamino), aminoalkyl (including 2-amino        isopropyl), dihydroxyalkyl (including 1,3-dihydroxy isopropyl,        1,2-dihydroxy ethyl), alkoxy (including methoxy), dialkylamino        (including dimethylamino), hydroxyalkyl (including 1-hydroxy        eth-2-yl), —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴ (including        —SO₂CH₃), —NH₂, or a 5 or six membered ring which contains at        least one heteroatom N and may optionally contain an additional        heteromoiety selected from S, SO₂, N, and O, and the 5 or 6        membered ring may be saturated, partially unsaturated or        aromatic (including piperidinyl, morpholinyl, imidazolyl, and        pyridyl) wherein aromatic nitrogen in the 5 or 6 membered ring        may be present as N-oxide (including pyridyl N-oxide), and the 5        or 6 membered ring may be optionally substituted with methyl,        halogen, alkylamino, or alkoxy (including 1 methyl imidazolyl);        R³ may also be absent, with the proviso that R³ is not absent        when E is nitrogen;

gg) R³ is

-   -   hydrogen, phenyl, 2-hydroxy ethylamino,        1-hydroxyeth-2-yl(methyl)amino, methylamino, 2-amino isopropyl,        1,3-dihydroxy isopropyl, 1,2-dihydroxy ethyl, methoxy,        dimethylamino, 1-hydroxy eth-2-yl, —COOH, —CONH₂, —CN, —SO₂—,        —SO₂CH₃), —NH₂, piperidinyl, morpholinyl, imidazolyl, pyridyl,        pyridyl N-oxide), or 1 methyl imidazolyl;

hh) R³ is

-   -   alkylamino (including methylamino), dialkylamino (including        dimethylamino), or —SO₂-alkyl-R⁴ (including —SO₂CH₃);

ii) R³ is

-   -   methylamino, dimethylamino, or —SO₂CH₃;

jj) R³ is

-   -   dimethylamino;

kk) R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl; and

ll) R⁴ is

-   -   hydrogen;        and all combinations of a) to 11), inclusive, herein above.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl, either of which may be substituted with one        of chloro, fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂,        —S(alkyl), —O(alkyl), or 4-aminophenyl;

W is

-   -   pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl, any of which may be connected through any carbon atom,        wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4        triazolyl, or furanyl may contain one —Cl, —CN, —NO₂, —OMe, or        —CF₃ substitution, connected to any other carbon;

R² is

-   -   cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl,        tetrahydropyridyl, or dihydropyranyl, any of which may be        independently substituted with one or two of each of the        following: chloro, fluoro, and C₍₁₋₃₎alkyl, with the proviso        that tetrahydropyridyl is connected to the ring A through a        carbon-carbon bond;

X is

and is oriented para with respect to —NHCO—W;

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;    -   Q_(a) is    -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,        aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered        ring which contains at least one heteroatom N and may optionally        contain an additional heteromoiety selected from S, SO₂, N, and        O, and the 5 or 6 membered ring may be saturated, partially        unsaturated or aromatic, wherein aromatic nitrogen in the 5 or 6        membered ring may be present as N-oxide, and the 5 or 6 membered        ring may be optionally substituted with methyl, halogen,        alkylamino, or alkoxy; R³ may also be absent, with the proviso        that R³ is not absent when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl;

W is

-   -   pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4 triazolyl, or        furanyl, any of which may be connected through any carbon atom,        wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4        triazolyl, or furanyl may contain one —Cl, —CN, —NO₂, —OMe, or        —CF₃ substitution, connected to any other carbon;

R² is

-   -   cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl,        tetrahydropyridyl, or dihydropyranyl, any of which may be        independently substituted with one or two of each of the        following: chloro, fluoro, and C₍₁₋₃₎alkyl, with the proviso        that tetrahydropyridyl is connected to the ring A through a        carbon-carbon bond;

X is

and is oriented para with respect to —NHCO—W;

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,        aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered        ring which contains at least one heteroatom N and may optionally        contain an additional heteromoiety selected from S, SO₂, N, and        O, and the 5 or 6 membered ring may be saturated, partially        unsaturated or aromatic, wherein aromatic nitrogen in the 5 or 6        membered ring may be present as N-oxide, and the 5 or 6 membered        ring may be optionally substituted with methyl, halogen,        alkylamino, or alkoxy; R³ may also be absent, with the proviso        that R³ is not absent when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl;

W is

-   -   3H-2-imidazolyl-4-carbonitrile;

R² is

-   -   cycloalkyl, thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl,        tetrahydropyridyl, or dihydropyranyl, any of which may be        independently substituted with one or two of each of the        following: chloro, fluoro, and C₍₁₋₃₎alkyl, with the proviso        that tetrahydropyridyl is connected to the ring A through a        carbon-carbon bond;

X is

and is oriented para with respect to —NHCO—W;

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,        aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered        ring which contains at least one heteroatom N and may optionally        contain an additional heteromoiety selected from S, SO₂, N, and        O, and the 5 or 6 membered ring may be saturated, partially        unsaturated or aromatic, wherein aromatic nitrogen in the 5 or 6        membered ring may be present as N-oxide, and the 5 or 6 membered        ring may be optionally substituted with methyl, halogen,        alkylamino, or alkoxy; R³ may also be absent, with the proviso        that R³ is not absent when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl;

W is

-   -   3H-2-imidazolyl-4-carbonitrile;

R² is

-   -   cyclohexenyl which may be substituted with one or two methyl        groups;

X is

and is oriented para with respect to —NHCO—W;

Z is

-   -   CH or N;

D¹ and D² are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D³ and D⁴ are

-   -   each hydrogen or taken together form a double bond to an oxygen;

D⁵ is

-   -   hydrogen or —CH₃, wherein said —CH₃ may be relatively oriented        syn or anti;        R_(a) and R_(b) are independently    -   hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl, or        heteroaralkyl;

E is

-   -   N, S, O, SO or SO₂, with the proviso that E may not be N if the        following three conditions are simultaneously met: Q_(a) is        absent, Q_(b) is absent, and R³ is an amino group or cyclic        amino radical wherein the point of attachment to E is N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —NH—, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that        Q_(b) may not be C(O) if Q_(a) is C(O), and further provided        that Q_(b) may not be —NH— if E is N and Q_(a) is absent,        further provided that Q_(b) may not be —NH— if R³ is an amino        group or cyclic amino radical wherein the point of attachment to        Q_(b) is N;

R³ is

-   -   hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,        aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered        ring which contains at least one heteroatom N and may optionally        contain an additional heteromoiety selected from S, SO₂, N, and        O, and the 5 or 6 membered ring may be saturated, partially        unsaturated or aromatic, wherein aromatic nitrogen in the 5 or 6        membered ring may be present as N-oxide, and the 5 or 6 membered        ring may be optionally substituted with methyl, halogen,        alkylamino, or alkoxy; R³ may also be absent, with the proviso        that R³ is not absent when E is nitrogen;

R⁴ is

-   -   hydrogen, —OH, alkoxy, carboxy, carboxamido, or carbamoyl.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl;

W is

-   -   3H-2-imidazolyl-4-carbonitrile;

R² is

-   -   cyclohexenyl which may be substituted with one or two methyl        groups;

X is

and is oriented para with respect to —NHCO—W;

Z is

-   -   CH;

D¹ and D² are

-   -   each hydrogen;

D³ and D⁴ are

-   -   each hydrogen;

D⁵ is

-   -   —CH₃, wherein said —CH₃ may be relatively oriented syn or anti;

E is

-   -   N;

Q_(a) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O);

Q_(b) is

-   -   absent, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that Q_(b)        may not be C(O) if Q_(a) is C(O), further provided that Q_(b)        may not be —NH— if R³ is an amino group or cyclic amino radical        wherein the point of attachment to Q_(b) is N;

R³ is

-   -   hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,        aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl,        —COOH, —CONH₂, —CN, —SO₂—CH₃, —NH₂, pyridyl, pyridyl-N-oxide, or        morpholinyl.

Other preferred embodiments of Formula I are those wherein:

A is

-   -   phenyl or pyridyl;

W is

-   -   3H-2-imidazolyl-4-carbonitrile;

R² is

-   -   cyclohexenyl which may be substituted with one or two methyl        groups;

X is

and is oriented para with respect to —NHCO—W.

Examples of compounds of Formula I include:

-   5-cyano-furan-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide,    and-   5-cyano-furan-2-carboxylic acid    [4-(4-methyl-piperazin-1-yl)-2-(2-methyl-thiophen-3-yl)-phenyl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Additional examples of compounds of Formula I include:

-   4-cyano-1H-imidazole-2-carboxylic acid    [4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide,-   5-cyano-furan-2-carboxylic acid    [2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide,-   5-cyano-furan-2-carboxylic acid    [2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide,-   5-cyano-furan-2-carboxylic acid    [2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide, and-   5-cyano-furan-2-carboxylic acid    [2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Further examples of compounds of Formula I are:

-   (4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic    acid,-   4-cyano-1H-imidazole-2-carboxylic acid    [4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl}-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide,-   4-cyano-1H-pyrrole-2-carboxylic acid    (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amide,    and-   4-cyano-1H-pyrrole-2-carboxylic acid    [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Other examples of compounds of Formula I are:

-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4-carbonyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl}-amide,-   4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic    acid amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide,-   4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylic    acid (2-hydroxy-ethyl)-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-3H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    (2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl}-amide,-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,    and-   4-cyano-1H-imidazole-2-carboxylic acid    [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Another example compound of Formula I is:

-   4-cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(1-{2-[(2-hydroxy-ethyl)-methyl-amino]-acetyl}-piperidin-4-yl)-phenyl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Another example compound of Formula I is:

-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Another example compound of Formula I is:

-   4-cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Still other example compounds of formula I are:

-   4-Cyano-1H-imidazole-2-carboxylic acid    {4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide    trifluoroacetic acid salt,-   4H-[1,2,4]-triazole-3-carboxylic acid    (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis    trifluoroacetic acid salt,-   5-Chloro-4H-[1,2,4]-triazole-3-carboxylic acid    (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic    acid salt,-   5-Cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide    bis trifluoroacetic acid salt,-   5-cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide    bis trifluoroacetic acid salt,-   5-Cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide,-   5-Cyano-1H-imidazole-2-carboxylic acid    [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide    trifluoroacetic acid salt,-   4-Cyano-1H-imidazole-2-carboxylic acid    [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide    trifluoroacetic acid salt,-   5-Cyano-1H-imidazole-2-carboxylic acid    {4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide    trifluoroacetic acid salt, and-   5-Cyano-1H-imidazole-2-carboxylic acid    [6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4]bipyridinyl-5-yl]-amide,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

Additional example compounds of Formula I are:

-   4-Cyano-1H-imidazole-2-carboxylic acid    {2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide,-   4-Cyano-1H-imidazole-2-carboxylic acid    [1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide    trifluoroacetic acid salt, and-   4-Cyano-1H-imidazole-2-carboxylic acid    [6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amide    trifluoroacetic acid salt,    and solvates, hydrates, tautomers and pharmaceutically acceptable    salts thereof.

As used herein, the term “the compounds of the present invention” shallalso include solvates, hydrates, tautomers or pharmaceuticallyacceptable salts thereof.

Pharmaceutically Acceptable Salts

As stated, the compounds of the present invention may also be present inthe form of pharmaceutically acceptable salts.

For use in medicines, the salts of the compounds of the presentinvention refer to non-toxic “pharmaceutically acceptable salts.” FDAapproved pharmaceutically acceptable salt forms (Ref. International J.Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977, January, 66(1), p 1)include pharmaceutically acceptable acidic/anionic or basic/cationicsalts.

Pharmaceutically acceptable acidic/anionic salts include, and are notlimited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate,bromide, calcium edetate, camsylate, carbonate, chloride, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate,tannate, tartrate, teoclate, tosylate and triethiodide. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

Pharmaceutically acceptable basic/cationic salts include, and are notlimited to aluminum, 2-amino-2-hydroxymethyl-propane-1,3-diol (alsoknown as tris(hydroxymethyl)aminomethane, tromethane or “TRIS”),ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calciumhydroxide, chloroprocaine, choline, choline bicarbonate, cholinechloride, cyclohexylamine, diethanolamine, ethylenediamine, lithium,LiOMe, L-lysine, magnesium, meglumine, NH₃, NH₄OH, N-methyl-D-glucamine,piperidine, potassium, potassium-t-butoxide, potassium hydroxide(aqueous), procaine, quinine, sodium, sodium carbonate,sodium-2-ethylhexanoate (SEH), sodium hydroxide, or zinc.

Prodrugs

The present invention also includes within its scope, prodrugs of thecompounds of the present invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into an active compound. Thus, in the methods of treatment of thepresent invention, the term “administering” shall encompass the meansfor treating, ameliorating or preventing a syndrome, disorder or diseasedescribed herein with the compounds of the present invention or aprodrug thereof, which would obviously be included within the scope ofthe invention albeit not specifically disclosed any given compound.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described in, for example, “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Stereochemical Isomers

One skilled in the art will recognize that some compounds of the presentinvention have one or more asymmetric carbon atoms in their structure.It is intended that the present invention include within its scopesingle enantiomer forms of the compounds of the present invention,racemic mixtures, and mixtures of enantiomers in which an enantiomericexcess is present.

The term “single enantiomer” as used herein defines all the possiblehomochiral forms which the compounds of the present invention and theirN-oxides, addition salts, quaternary amines, and physiologicallyfunctional derivatives may possess.

Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereoselectivereactions.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Suchsubstances have the same number and kind of atoms but differ instructure. The structural difference may be in constitution (geometricisomers) or in an ability to rotate the plane of polarized light(enantiomers).

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers.

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image.

The term “enantiomer” refers to one of a pair of molecular species thatare mirror images of each other and are not superimposable.

The term “diastereomer” refers to stereoisomers that are not mirrorimages.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s).

The term “racemate” or “racemic mixture” refers to a compositioncomposed of equimolar quantities of two enantiomeric species, whereinthe composition is devoid of optical activity.

The term “homochiral” refers to a state of enantiomeric purity.

The term “optical activity” refers to the degree to which a homochiralmolecule or nonracemic mixture of chiral molecules rotates a plane ofpolarized light.

It is to be understood that the various substituent stereoisomers,geometric isomers and mixtures thereof used to prepare the compounds ofthe present invention are either commercially available, can be preparedsynthetically from commercially available starting materials or can beprepared as isomeric mixtures and then obtained as resolved isomersusing techniques well-known to those of ordinary skill in the art.

The isomeric descriptors “R,” and “S” are used as described herein forindicating atom configuration(s) relative to a core molecule and areintended to be used as defined in the literature (IUPAC Recommendationsfor Fundamental Stereochemistry (Section E), Pure Appl. Chem., 1976,45:13-30).

The compounds of the present invention may be prepared as an individualisomer by either isomer-specific synthesis or resolved from an isomericmixture. Conventional resolution techniques include forming the freebase of each isomer of an isomeric pair using an optically active salt(followed by fractional crystallization and regeneration of the freebase), forming an ester or amide of each of the isomers of an isomericpair (followed by chromatographic separation and removal of the chiralauxiliary) or resolving an isomeric mixture of either a startingmaterial or a final product using preparative TLC (thin layerchromatography) or a chiral HPLC column.

Polymorphs and Solvates

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, the compounds mayform solvates, for example with water (i.e., hydrates) or common organicsolvents. As used herein, the term “solvate” means a physicalassociation of the compounds of the present invention with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. The term “solvate” is intended to encompass bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.

It is intended that the present invention include within its scopesolvates of the compounds of the present invention. Thus, in the methodsof treatment of the present invention, the term “administering” shallencompass the means for treating, ameliorating or preventing a syndrome,disorder or disease described herein with the compounds of the presentinvention or a solvate thereof, which would obviously be included withinthe scope of the invention albeit not specifically disclosed.

N-Oxides

The compounds of the present invention may be converted to thecorresponding N-oxide form following art-known procedures for convertinga trivalent nitrogen into its N-oxide form. Said N-oxidation reactionmay generally be carried out by reacting the starting material with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tbutyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Tautomeric Forms

The compounds of the present invention may also exist in theirtautomeric forms. Such forms although not explicitly indicated in thepresent application are intended to be included within the scope of thepresent invention.

Preparation of the Compounds of the Present Invention

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protecting Groups, P. Kocienski, Thieme Medical Publishers,2000; and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3^(rd) ed. Wiley Interscience, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art.

Methods of Preparation

Scheme 1 illustrates general methodology for the preparation ofcompounds of Formula I. Compounds of Formula 1-2 can be obtained byortho-halogenation, preferably bromination, of amino compounds ofFormula 1-1 followed by metal-catalyzed coupling reactions with boronicacids or boronate esters (Suzuki reactions, where R²M is R²B(OH)₂ or aboronic ester) or tin reagents (Stille reactions, where R²M isR²Sn(alkyl)₃) (for reviews, see N. Miyaura, A. Suzuki, Chem. Rev.,95:2457 (1995), J. K. Stille, Angew. Chem, Int. Ed. Engl., 25: 508024(1986) and A. Suzuki in Metal-Catalyzed Coupling Reactions, F.Deiderich, P. Stang, Eds., Wiley-VCH, Weinheim (1988)). Compounds offormula 1-1 may be commercially available, or the above palladiummediated cross-coupling reactions described above may be used togenerate compounds of Formula 1-1 from starting material 1-0.

Preferred conditions for the bromination of 1-1 are N-bromosuccinimide(NBS) in a suitable solvent such as N,N-dimethylformamide (DMF),dichloromethane (DCM) or acetonitrile. Metal-catalyzed couplings,preferably Suzuki reactions, can be performed according to standardmethodology, preferably in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), an aqueous basesuch aq. Na₂CO₃, and a suitable solvent such as toluene, ethanol,dimethoxyethane (DME), or DMF.

Compounds of Formula I can be prepared by reaction of compounds ofFormula 1-2 with carboxylic acids WCOOH according to standard proceduresfor amide bond formation (for a review, see: M. Bodansky and A.Bodansky, The Practice of Peptide Synthesis, Springer-Verlag, NY (1984))or by reaction with acid chlorides WCOCl or activated esters WCO₂Rq(where Rq is a leaving group such as pentafluorophenyl orN-succinimide). The preferred reaction conditions for coupling withWCOOH are: when W is a furan, oxalyl chloride in DCM with DMF as acatalyst to form the acid chloride WCOCl and then coupling in thepresence of a trialkylamine such as DIEA; when W is a pyrrole,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and1-hydroxybenzotriazole-6-sulfonamidomethyl hydrochloride (HOBt); andwhen W is an imidazole, the preferred conditions arebromotripyrrolidinophos-phonium hexafluorophosphate (PyBrOP) anddiisopropylethylamine (DIEA) in DCM.

It is understood that the optional substitution present on ring A inFormula I may be present in the starting materials 1-1 or 1-3 and, insuch cases, would be carried through the synthesis outlined in Scheme 1.Alternatively various substituents on compounds of Formula I may beintroduced in a number of ways described below to provide the optionalsubstitution listed for Formula I. The leaving group “L₁” present onring A in Formula 1-0 or 1-3, can be substituted before or at any stepduring Scheme 1. When such leaving groups (preferably fluoro or chloro)are activated by the nitro group of Formula 1-3 for nucleophilic attack,they can undergo direct nucleophilic aromatic substitution by ammoniaand azide anion or by amines, alcohols, thiols and other nucleophiles inthe presence of a suitable base such as K₂CO₃, N,N-diisopropylethylamine(DIEA) or NEt₃. When the leaving group is suitable for metal-catalyzedcouplings (preferably bromo or trifluoromethane-sulfonyloxy), a numberof cross-coupling reactions (such as Suzuki or Stille reactions asdiscussed above for the introduction of R²) may be performed. Othermetal-catalyzed coupling reactions that can be employed include aromaticand heteroaromatic amination and amidation (for reviews, see: S. L.Buchwald, et al, Top. Curr. Chem., 219:131-209 (2001) and J. F. Hartwigin “Organopalladium Chemistry for Organic Synthesis,” WileyInterscience, NY (2002). Additional metal catalyzed cross couplingreactions with 2,4,6-trimethyl-cyclotriboroxane may be employed if L₁ isbromo, iodo, or chloro activated by nitro to generate optional methylsubstitution (see M. Gray, et al, Tetrahedron Lett., 41: 6237-40(2000)).

In some cases, the initial substituents can be further derivatized asdescribed below to provide the final substitution of Formula I.

An alternative method for the introduction of nitrogen-containingheterocyclic substituents onto ring A is to form the heterocycle from anamino group on ring A. The amino group may be originally present in thestarting material in a protected or unprotected form or may result fromthe reduction of a nitro group which also can be either originallypresent in the starting material or attached by a nitration reaction. Inaddition, the amino group may be formed by reduction of an azide groupwhich can be present in the starting material or may result fromnucleophilic aromatic substitution of an activated halide by azide anionas mentioned above. The amino group may also result from nucleophilicaromatic substitution of an activated halide (m, for example a nitrohalocompound) by ammonia or by the anion of a protected ammonia equivalent,for example, t-butyl carbamate. If introduced in protected form, theamine can be deprotected according to standard literature methods. (Forexamples of amine protecting groups and deprotection methods see:Theodora W. Greene and Peter G. M. Wuts, John Wiley and Sons, Inc., NY(1991).) The ring-forming reaction involves treatment of the anilineamino group with a suitable optionally substituted di-electrophile,preferably a dihalide or dicarbonyl compound, which results in twosubstitutions on the amino group to form an optionally substitutedheterocycle. In the case of dihalides, any of a number of suitable basescan be added as an acid scavenger such as potassium carbonate, sodiumhydroxide, or, a trialkylamine such as triethylamine Thus, treatmentwith a bis(2-haloethyl)amine such as bis(2-chloroethyl)amine orbis(2-bromoethyl)amine would afford a piperazine ring (see, for example,J. Med. Chem., 29: 640-4 (1986) and J. Med. Chem., 46: 2837 (2003)).Optional substitution on the amine nitrogen of the reagent wouldincorporate optional substitution on the terminal amine of thepiperazine. For example, treatment with N,N-bis(2-chloroethyl)anilinewould give an N-phenylpiperazino group. Treatment with abis(2-haloethyl)ether or bis(2-haloethyl)thioether would afford amorpholine or thiomorpholine ring, respectively.

Another alternative method to direct substitution to introduceheterocyclic substituents onto ring A is to form the heterocycle from analdehyde (i.e. from a formyl group on ring A). The formyl group may beoriginally present in the starting material in a protected orunprotected form or may result from or any of a number of formylationreactions known in the literature including a Vilsmeier-Haack reaction(for a review of formylation chemistry, see: G. A. Olah, et al, Chem.Rev., 87: (1987)) or by para-formylation of nitroaromatics (see: A.Katritsky and L. Xie, Tetrahedron Lett., 37:347-50 (1996)).

Finally it is understood that compounds of Formula I may be furtherderivatized. Protecting groups on compounds of Formula I can be removedaccording to standard synthetic methodologies (Theodora W. Greene andPeter G. M. Wuts, John Wiley and Sons, Inc., NY (1991)) and can be thensubjected to further derivatization. Examples of further derivatizationof compounds of I include, but are not limited to: when compounds ofFormula I contain a primary or secondary amine, the amine may be reactedwith aldehydes or ketones in the presence of a reducing agent such assodium triacetoxyborohydride (see Abdel-Magid J. Org. Chem. 61, pp.3849-3862, (1996)) to reductively alkylate; with acid chlorides orcarboxylic acids and an amide bond forming reagent as described above toform amides; with sulfonyl chlorides to form sulfonamides; withisocyanates to form ureas; with aryl- or heteroaryl-halides in thepresence of a palladium catalyst as described above (see Buchwald andHartwig references above) to form aryl and heteroarylamines. Inaddition, when compounds of Formulae I contain an aryl halide orheteroaryl halide, these compounds may be subjected to metal-catalyzedreactions with boronic acids (for example, Suzuki or Stille couplings asdescribed above), or, amines or alcohols (Buchwald- or Hartwig-typecouplings, see Buchwald and Hartwig references above). When compounds ofFormulae I contain a cyano group, this group may be hydrolyzed to amidesor acids under acid or basic conditions. Basic amines may be oxidized toN-oxides and conversely N-oxides may be reduced to basic amines Whencompounds of Formula I contain a sulfide, either acyclic or cyclic, thesulfide can be further oxidized to the corresponding sulfoxides orsulfones. Sulfoxides can be obtained by oxidation using an appropriateoxidant such as one equivalent of (meta-chloroperbenzoicacid) MCPBA orby treatment with NaIO₄ (see, for example, J. Regan, et al, J. Med.Chem., 46: 4676-86 (2003)) and sulfones can be obtained using twoequivalents of MCPBA or by treatment with 4-methylmorpholine N-oxide andcatalytic osmium tetroxide (see, for example, PCT application WO01/47919).

Scheme 2a illustrates a route to compounds of Formula I. F represents—NQ_(a)Q_(b)R³—, —O—, S, SO, or SO₂, and AA represents —NH₂ or —NO₂. D¹and D² are shown for illustrative purposes only; it is recognized bythose skilled in art that D⁵ D⁶ D⁷ D⁸ may also be present. Ketones offormula 2-1 can be converted to a vinyl triflate of formula 2-2 bytreatment with a non-nucleophilic base such as LDA and then trapping ofthe resulting enolate with a triflating reagent such astrifluoromethanesulfonic anhydride or preferablyN-phenyltrifluoromethanesulfonimide. Suzuki coupling of boronic acids orboronate esters of formula 2-3 to vinyl triflates of formula 2-2 canprovide compounds of formula 2-4 where Z is C (Synthesis, 993 (1991)).

For compounds of formula 2-4 treatment with Pd/C can reduce both theolefin (and the nitro if AA is NO₂) to give Z is CH, AA is NH₂.Compounds of formula 2-4 where F represents —SO₂ can be prepared fromcompounds of formula 2-4 where AA is —NO₂ and F is a sulfide (F is —S—)by oxidation with MCPBA or other methods described in Scheme 1. Thenitro group may then be reduced with Pd/C to reduce both the nitro andthe olefin.

Compounds of formula 2-4 (AA is NH₂) are then converted to compounds ofFormula 2-5 (which also represent compounds of Formulae I if no furthermodifications are required) as described in Scheme 1.

Compounds of formula 2-5 may be further modified to provide additionalcompounds of Formula I. For example, in cases where F is—NQ_(a)Q_(b)R³—, Q_(a)Q_(b) is a direct bond, and R₃ represents a BOCprotecting group (CO₂tBu), the BOC group may be removed according tostandard methodology such as trifluoroactic acid (TFA) in DCM (Greeneand Wuts, ibid.) to provide a secondary amine that can then be furtherderivatized to provide compounds of Formula I. Further derivatizationincludes, but is not limited to: reactions with aldehydes or ketones inthe presence of a reducing agent such as sodium triacetoxyborohydride toprovide compounds of Formula II where F is —NCH₂R³ (A. F. Abdel-Magid,ibid.); with acid chlorides or with carboxylic acids and an amide bondforming reagent (as described in Scheme 1) to provide compounds ofFormula II where F is —NCOR³; with sulfonyl chlorides (as described inScheme 1) to provide compounds of Formula I where F is —NSO₂R_(a); withisocyanates (as described in Scheme 1) to provide compounds of FormulaII where F is —NCONR_(a)R_(b); or subjected to metal-catalyzedsubstitution reactions as outlined in Scheme 1 to provide compounds ofFormula I where F is —NR³. (S. L. Buchwald, et al, ibid.; J. H. Hartwig,ibid.) For the above example, R_(a) and R_(b) are independentlyhydrogen, alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, heteroaryl andheteroaralkyl.

Scheme 2b illustrates a modification of Scheme 2a to synthesizepartially unsaturated compounds of Formula I. E represents—NQ_(a)Q_(b)R³, —O— (D¹ and D² are H), —S— (D¹ and D² are H), -(D¹ andD² are H), or —SO₂— (D¹ and D² are H), and R₁ represents —NH₂ or —NO₂.Compounds of formula 2-4 are prepared as shown in Scheme 2. If R₁ is—NO₂, the nitro group must be reduced by a method that does not reduceolefins, such as iron and ammonium chloride. If R_(AA) of formula 2-4 isan amino group then no step is necessary and compounds of formula 2-4are also compounds of formula 2-7. To prepared compounds of formula 2-7where E is —SO₂— or —SO—, the oxidation of the sulfide must be performedon compound 2-4 where R₁ is —NO₂ as described above, followed by nitroreduction.

Scheme 3 illustrates the preparation of intermediates for the synthesisof compounds of Formula I, where ring A is pyridyl, and R⁵ is theoptional substitution on ring A or one of the heterocyclic substituentsas defined in Formula I. K is NH₂ or other functional groups such asNO₂, COOH or COOR which can eventually be converted to amino group byknown literature methods such as reductions for NO₂ (as discussed forScheme 1) or Curtius rearrangement for COOH (for a review, see OrganicReactions, 3: 337 (1947)). L³ and L⁴ are halogens. (K is COOH can alsobe formed from K is COOR by simple base- or acid-catalyzed hydrolysis.)In general, the selectivity and order in introducing R² and R⁵ can beachieved by the relative reactivity of the halogens L³ and L⁴ chosen incompound (3-1), the intrinsic selectivity of the heterocycle and/or thereaction conditions employed. An example of using the relativereactivity of the halogens L³ and L⁴ in selectively introducing R² andR⁵ would include the situation where, in compounds of Formula 3-1 whereL³ is a fluoro group and L⁴ is a bromo group, selective displacement ofthe fluoro group by a nucleophile can be achieved followed bysubstitution of the remaining bromo group by metal-catalyzedsubstitution chemistry (such as Suzuki or Stille cross-couplingreactions as further outlined below). Similarly in compounds of Formula3-1 where one of L³ and L⁴ is an iodo group and the other is a bromo orchloro group, selective metal-catalyzed substitution chemistry (such asSuzuki or Stille cross-coupling reactions or Buchwald/Hartwig aminationsas further discussed below) on the iodo group can be achieved followedby replacement of the remaining bromo or chloro group by anothermetal-catalyzed substitution reaction.

As illustrated in Scheme 3, leaving group L³ in Formula 3-1 can be firstsubstituted to obtain compounds of Formula 3-3 or leaving group L⁴ canbe first substituted to obtain compound of Formula 3-2. Compounds 3-2 or3-3 can then be reacted to displace L³ or L⁴ to furnish the compound ofFormula 3-4.

Thus, a direct nucleophilic displacement or metal-catalyzed amination ofcompound of Formula 3-1 with a secondary amine, ammonia or a protectedamine such as ten-butyl carbamate (for review, see Modern AminationMethods: Ricci, A., Ed.; Wiley-VCH: Weinheim, 2000), can be used tointroduce R⁵ in Formulae 3-2 or 3-3 where R⁵ is a primary or secondaryamine, amino group (NH₂), and amine equivalent or a protected aminogroup. Metal-catalyzed coupling of compound 3-1 with boronic acids orboronates esters (Suzuki reaction, M is boronic acid group or boronateester group) or with organotin compounds (Stille reaction, M is SnR₃,where R is alkyl and the other substituents as defined above, asdescribed in Scheme 1 can provide compounds of Formulae 3-2 or 3-3.

Compound 3-2 can be further converted to compound 3-4 by ametal-catalyzed Suzuki or Stille coupling as described above. L⁴ incompound 3-3 also subsequently can be substituted with R⁵ to obtaincompounds of Formula 3-4, again, by a direct nucleophilic substitutionor metal-catalyzed reaction with a nucleophile or by the samemetal-catalyzed cross-coupling reaction as described above. When R⁵ inthe formulae (3-2, 3-3 or 3-4) is a protected amine and K not an aminogroup, it can be deprotected to unmask the amino functionality. Thisamino functionality can then be further derivatized as described inScheme 1. When the K group in Formula 3-4 is not an amino group (such asfunctionality described above), it can be converted to an amino groupaccording to known literature methods (see, for example ComprehensiveOrganic Transformations Larock, R. S.; Wiley and Sons Inc., USA, 1999)and the resulting amine 3-5 can be employed in amide bond formationreactions as described in Scheme (1) to obtain the compounds in FormulaI. When K in Formula 3-4 is an amino group it can be directly used inamide coupling as described above.

Schemes 4a and 4b illustrate the preparation of intermediates to befurther modified according to Scheme 3 starting from amonohalo-substituted compound of Formulae 4-1 and 4-5 by introducing thesecond leaving group after the replacement of the first one has beencompleted. These can also be used for the synthesis of compounds ofFormula I where ring A is a pyridine and R⁵ is either the optionalsubstitution on Ring A or one of the heterocyclic substituents. As inScheme 3, the remaining positions on the pyridine ring can besubstituted as described in Formula I. K is NH₂ or other functionalgroups such as NO₂, COOH or COOR which can eventually be converted toamino group by known literature methods such as reductions or Curtiusrearrangement as described in Scheme 3. L³ and L⁴ are halogens. In thesecompounds, T is either H or is a functional group such as OH that can beconverted to leaving groups L³ or L⁴ such as halogen, triflate ormesylate by known literature methods (see, for example, Nicolai, E., etal., J. Heterocyclic Chemistry, 31, (73), (1994)). Displacement of L³ incompound of Formula 4-1 or L⁴ in Formula 4-5 by methods described inScheme 3, can yield compounds of Formulae 4-2 and 4-6. At this point,the substituent T of compounds 4-2 or 4-6 can be converted to a leavinggroup L⁴ or L³ (preferably a halogen) by standard methods to providecompounds of Formulae 4-3 and 4-5. For example, when T is OH, thepreferred reagents to effect this transformation are thionyl chloride,PCl₅, POCl₃ or PBr₃ (see, for examples, Kolder, den Hertog., Recl. Trav.Chim. Pays-Bas; 285, (1953), and Iddon, B, et. al., J. Chem. Soc. PerkinTrans. 1, 1370, (1980)). When T is H, it can be directly halogenated(preferably brominated) to provide compounds of Formulae 4-3 or 4-7(see, for example, Canibano, V. et al., Synthesis, 14, 2175, (2001)).The preferred conditions for bromination are NBS in a suitable solventsuch as DCM or acetonitrile.

The compounds of Formulae 4-3 or 4-7 can be converted to compounds ofFormulae 4-4 or 4-8 by introduction of the remaining groups R² or R⁵,respectively, by the methods described above and then on to compounds ofFormula I, by the methods described in Scheme 3 for conversion ofcompounds of Formulae 3-4 and 3-5 to compounds of Formula I.

Representative compounds of the present invention and their synthesisare presented in the following chart and examples thereafter. Thefollowing are for exemplary purposes only and are in no way meant tolimit the invention. Preferred compounds of the present invention areExamples 5, 17, 23, 34, 38, and 51. Preferred examples of inhibitors ofC-KIT are 51a, 48, 52, 55, and 26.

Name Structure  4 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2- (3-methyl-thiophen-2-yl)- phenyl]-amide

 5 5-Cyano-furan-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)- phenyl]-amide

 6 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-1- hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amide trifluoroacetic acid salt

 7 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl- acetyl)-piperidin-4-yl]-phenyl}- amide

 8 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl- propionyl)-piperidin-4-yl]- phenyl}-amide

 9 5-Cyano-furan-2-carboxylic acid [2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

10 5-Cyano-furan-2-carboxylic acid [2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

11 5-Cyano-furan-2-carboxylic acid [2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

12 5-Cyano-furan-2-carboxylic acid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)- phenyl-amide

13 4-Cyano-1H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt

14 4-Cyano-1H-imidazole-2- carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)- amide trifluoroacetic acid salt

15 4-Cyano-1H-pyrrole-2-carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide

16 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1- enyl-phenyl]-amide

17 4-Cyano-1H-imidazole-2- carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4- yl-phenyl]-amide trifluoroacetic acidsalt

18 4-Cyano-1H-imidazole-2- carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)- amide trifluoroacetic acid salt

20 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl- acetyl)-piperidin-4-yl]-phenyl}- amide

21 4-Cyano-1H-imidazole-2- carboxylic acid [2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl- piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

22 4-Cyano-1H-imidazole-2- carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2- ylmethyl-piperidin-4-yl)-phenyl]- amidetrifluoroacetic acid salt

23 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol- 2-ylmethyl)-piperidin-4-yl]-phenyl}-amide trifluoroacetic acid salt

24 4-{4-[(4-Cyano-1H-imidazole-2- carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1- carboxylic acid amide

25 4-Cyano-1H-imidazole-2- carboxylic acid [2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-4-yl)-phenyl}- amidetrifluoroacetic acid salt

26 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)- piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

27 4-Cyano-1H-imidazole-2- carboxylic acid {4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex- 1-enyl-phenyl}-amide trifluoroaceticacid salt

28 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1-carbamoylmethyl-piperidin-4-yl)- 2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt

29 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)- piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

30 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)- piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

31 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)- piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

32 4-Cyano-1H-imidazole-2- carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H- imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt

33 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-1H-imidazol-4-yl- acetyl)-piperidin-4-yl]-phenyl}- amidetrifluoroacetic acid salt

34 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl- ethyl)-piperidin-4-yl]-phenyl}- amidedi-trifluoroacetic acid salt

35 4-Cyano-1H-imidazole-2- carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran- 4-yl)-4-piperidin-4-yl-phenyl]- amide

36 4-Cyano-1H-imidazole-2- carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran- 4-yl)-4-piperidin-4-yl-phenyl]- amidetrifluoroacetic acid salt

37 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo- 1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

38 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-dimethylamino- acetyl)-piperidin-4-yl]-phenyl}- amide

 38b 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methylamino- acetyl)-piperidin-4-yl]-phenyl}- amide

39 4-{4-[(4-Cyano-1H-imidazole-2- carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1- carboxylic acid (2-hydroxy- ethyl)-amide

40 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl- ethyl)-piperidin-4-yl]-phenyl}- amide

41 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4- carbonyl)-piperidin-4-yl]- phenyl}-amide

42 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3- carbonyl)-piperidin-4-yl]- phenyl}-amide

43 4-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)- piperidin-4-yl]-phenyl}-amide

44 4-Cyano-1H-imidazole-2- carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy- ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt

45 4-Cyano-1H-imidazole-2- carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethyl)- methyl-amino-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt

46 4-Cyano-1H-imidazole-2- carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6- tetrahydro-pyridin-3-yl)-phenyl]- amidetrifluoroacetic acid salt

47 (4-{4-[(4-Cyano-1H-imidazole-2- carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)- acetic acid trifluoroacetic acid salt

48 4-Cyano-1H-imidazole-2- carboxylic acid {4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2- cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

49 4H-[1,2,4]-triazole-3-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroacetic acid salt

50 5-Chloro-4H-[1,2,4]-triazole-3- carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)- amide trifluoroacetic acid salt

 51a 5-Cyano-1H-imidazole-2- carboxylic acid [2-cyclohex-1-enyl-4-(cis-2,6-dimethyl- piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt

 51b 5-cyano-1H-imidazole-2- carboxylic acid [2-cyclohex-1-enyl-4-(trans-2,6-dimethyl- piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt

52 5-Cyano-1H-imidazole-2- carboxylic acid {2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy- propionyl)-piperidin-4-yl}-phenyl}-amide

53 5-Cyano-1H-imidazole-2- carboxylic acid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4- yl)-phenyl]-amide trifluoroacetic acidsalt

54 4-Cyano-1H-imidazole-2- carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′- hexahydro-[2,4′]bipyridinyl-5-yl]-amide trifluoroacetic acid salt

55 4-Cyano-1H-imidazole-2- carboxylic acid [1′-(2-dimethylamino-acetyl)-6-(4,4- dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro- [2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

56 4-Cyano-1H-imidazole-2- carboxylic acid [6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2- methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro- [2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

57 5-Cyano-1H-imidazole-2- carboxylic acid {4-[1-(2-amino-2-methyl-propionyl)-piperidin-4- yl]-2-cyclohex-1-enyl-phenyl}- amidetrifluoroacetic acid salt

58 5-Cyano-1H-imidazole-2- carboxylic acid [6-cyclohex-1-enyl-1′-(2-methanesulfonyl- ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide

Example 1 5-Cyano-furan-2-carboxylic acid

To a flask with a stir bar and Vigreaux column under Ar was added2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol), hydroxylaminehydrochloride (2.7 g, 40 mmol), and dry pyridine (50 mL). The mixturewas heated to 85° C., acetic anhydride (40 mL) was added and the mixturewas stirred for 3 h. After cooling to 60° C., water (250 mL) was addedand the mixture was stirred at RT for 70 h. The mixture was acidified topH 2 with concentrated hydrochloric acid and extracted with 3:1dichloromethane-isopropanol (8×100 mL). The combined organic layers werewashed with water (100 mL), brine (100 mL), dried over anh sodiumsulfate and concentrated in vacuo to afford the title compound as a tansolid (1.26 g, 46%). ¹H-NMR (CD₃OD; 400 MHz): δ 14.05 (br s, 1H), 7.74(d, 1H, J=3.8 Hz), 7.42 (d, 1H, J=3.8 Hz).

Example 2 4-Cyano-1H-pyrrole-2-carboxylic acid

The title compound was prepared by the literature procedure (Loader andAnderson, Canadian J. Chem. 59: 2673 (1981)). ¹H-NMR (CDCl₃; 400 MHz): δ12.70 (br s, 1H), 7.78 (s, 1H), 7.13 (s, 1H).

Example 34-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A flask charged with imidazole-4-carbonitrile (0.5 g, 5.2 mmol)(Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl)(0.95 mL, 5.3 mmol), K₂CO₃ (1.40 g, 10.4 mmol), and acetone (5 mL) wasstirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) andwashed with water (20 mL) and brine (20 mL) and the organic layer driedover MgSO₄. The crude product was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the titlecompound as a colorless oil. Mass spectrum (CI (CH₄), m/z) Calcd. forC₁₀H₁₇N₃OSi, 224.1 (M+H). found 224.1.

b)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.70 g,3.1 mmol) (as prepared in the previous step) in CCl₄ (10 mL) was addedNBS (0.61 g, 3.4 mmol) and AIBN (cat), and the mixture heated at 60° C.for 4 h. The reaction was diluted with EtOAc (30 mL) and washed withNaHCO₃ (2×30 mL) and brine (30 mL) and the organic layer was dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.73 g (77%) of ayellow solid. Mass spectrum (CI (CH₄), m/z) Calcd. for C₁₀H₁₆BrN₃OSi,302.0/304.0 (M+H). found 302.1/304.1.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

To a solution of2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile(0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at−40° C. was added drop wise a solution of 2M i-PrMgCl in THF (1 mL). Thereaction was allowed to stir for 10 min at −40° C. and then cooled to−78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. Thereaction allowed to attain RT and stirred for 1 h. The reaction wasquenched with satd aq NH₄Cl, diluted with EtOAc (20 mL) and washed withbrine (2×20 mL), and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was eluted from a 20-g SPE cartridge(silica) with 30% EtOAc/hexane to give 0.4 g (74%) of a colorless oil.Mass spectrum (ESI, m/z): Calcd. for C₁₃H₂₁N₃O₃Si, 296.1 (M+H). found296.1.

d)4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester (0.4 g, 1.3 mmol) (as prepared in the previous step) inethanol (3 mL) was added a solution of 6M KOH (0.2 mL) and the reactionwas stirred for 10 min and then concentrated to give 0.40 g (100%) ofthe title compound as a yellow solid. ¹H-NMR (400 MHz, CD₃OD) δ 7.98 (s,1H), 5.92 (s, 2H), 3.62 (m, 2H), 0.94 (m, 2H), 0.00 (s, 9H). Massspectrum (ESI-neg, m/z) Calcd. for C₁₁H₁₇N₃O₃Si, 266.1 (M−H). found266.0.

Example 4 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide

a) 1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine

2-Bromo-4-fluoronitrobenzene (949 mg, 4.31 mmol) was added in twoportions to neat N-methypiperazine (8 mL) at 0° C. and allowed to warmto room temperature. The reaction was heated to 60° C. for 1 h, and thenit was diluted with 50 mL of EtOAc and poured into H₂O (50 mL). Thelayers were separated and the organic layer was washed with satd aqNaHCO₃, dried (Na₂SO₄), and concentrated in vacuo to afford 580 mg (45%)of the title compound as a yellow solid: Mass spectrum (ESI, m/z):Calcd. for C₁₁H₁₄BrN₃O₂, 300.0 (M+H). found 300.1.

b) 4,4,5,5-Tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane

To a stirred solution of 2-bromo-3-methylthiophene (337 mg, 1.9 mmol) in8 mL of THF at −40° C. was added n-BuLi (0.8 mL, 2.5 M/hexanes), and thereaction was allowed to stir for 30 min. At this time2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol)was added, and the reaction was allowed to warm to ambient temperature,and stirring was continued for 1 h. The reaction was then cooled to 0°C. and quenched with satd aq NaHCO₃ (10 mL). The mixture was poured intoEtOAc (100 mL), washed with H₂O (2×50 mL), dried (Na₂SO₄) andconcentrated in vacuo. Purification of the residue by silica gelpreparative thin layer chromatography (20% EtOAc-hexanes) afforded 224mg (53%) of the title compound as an oil. ¹H-NMR (CDCl₃; 400 MHz): δ1.36 (s, 12H), 2.5 (s, 3H), 6.99 (d, 1H, J=4.8 Hz), 7.50 (d, 1H, J=4.8Hz).

c) 1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine

To a flask containing 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (68mg, 0.2 mmol, as prepared in Example 4, step (a)),4,4,5,5-tetramethyl-2-(3-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane (61mg, 0.27 mmol, as prepared in the previous step) and Pd(PPh₃)₄ (14 mg, 6mol %) was charged toluene (3 mL), ethanol (3 mL) and 2M Na₂CO₃ (4 mL).The resultant mixture was heated at 80° C. for 2 h and then poured intoEtOAc (25 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel preparative thin layerchromatography (EtOAc) afforded 40 mg (63%) of the title compound as alight yellow solid. Mass spectrum (ESI, m/z): Calcd. for C₁₆H₁₉N₃O₂S,318.1 (M+H). found 318.2.

d) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenyl]-amide

1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg5% Pd—C in MeOH (5 mL) under H₂ (1 atm) for 2 h. The reaction wasfiltered through Celite and concentrated in vacuo to afford 40 mg (72%)of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine asa brown solid, which was used immediately without further purification.Using a procedure similar to Example 9, step (c),4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonylchloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in thepresence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the titlecompound as a yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 2.13 (s, 3H),2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8Hz), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H),8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₂N₄O₂S, 407.1 (M+H). found 407.1.

Example 5 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenyl]-amide

a) 4,4,5,5-Tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane

Using a procedure similar to Example 4, step (b),3-bromo-4-methylthiophene (571 mg, 3.2 mmol) was treated with n-BuLi(1.41 mL, 2.5M/hexanes) and then allowed to react with2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (775 μL, 3.8 mmol)to afford 189 mg (26%) of the title compound as a colorless oil. ¹H-NMR(CDCl₃; 400 MHz): δ 1.32 (s, 12H), 2.42 (s, 3H), 6.90-6.91 (m, 1H), 7.84(d, 1H, J=2.9 Hz).

b) 1-Methyl-4-[3-(4-methyl-thiophen-3-yl)-4-nitro-phenyl]-piperazine

Using a procedure similar to Example 4, step (c),1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (162 mg, 0.54 mmol),4,4,5,5-tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (145mg, 0.64 mmol) and Pd(PPh₃)₄ (37 mg, 6 mol %) were allowed to react toafford 108 mg (71%) of the title compound as a yellow solid. ¹H-NMR(CDCl₃; 400 MHz): δ 2.02 (s, 3H), 2.37 (s, 3H), 2.55-2.57 (m, 4H),3.42-3.45 (m, 4H), 6.66 (d, 1H, J=2.8 Hz), 6.87 (s, 1H), 6.99-7.00 (m,1H), 7.09 (d, 1H, J=3.2 Hz), 8.13 (d, 1H, J=9.2 Hz).

c) 4-(4-Methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenylamine

Using a procedure similar to Example 4, step (d),1-methyl-4-[3-(4-methyl-thiophen-3-yl)-4-nitro-phenyl]-piperazine (100mg, 0.32 mmol) was stirred with 80 mg 5% Pd—C under H₂ to afford 82 mg(89%) of the title compound as a dark oil, which was used immediatelywithout further purification spectrum (ESI, m/z): Calcd. for C₁₆H₂₁N₃S,288.15 (M+H). found 288.1.

d) 5-Cyano-furan-2-carboxylic acid[4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenyl]-amide

Using a procedure similar to Example 9, step (c),5-cyano-furan-2-carbonyl chloride (64 mg, 0.41 mmol, as prepared inExample 9, step (c)) was allowed to react with4-(4-methyl-piperazin-1-yl)-2-(4-methyl-thiophen-3-yl)-phenylamine (80mg, 0.27 mmol, as prepared in the previous step) in the presence of DIEA(0.10 mL, 0.59 mmol) to afford 25.8 mg (24%) of the title compound as ayellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 2.09 (s, 3H), 2.37 (s, 3H),2.59-2.60 (m, 4H), 3.24-3.26 (m, 4H), 6.83 (d, 1H, J=2.9 Hz), 6.98-7.06(m, 2H), 7.14-7.21 (m, 3H), 7.96 (s, 1H), 8.32 (d, 1H, J=9.0 Hz). Massspectrum (ESI, m/z): Calcd. for C₂₂H₂₂N₄O₂S, 407.1 (M+H). found 407.1.

Example 6 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

a) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2,2-dimethyl-[1,3]dioxan-5-yl)-piperidin-4-yl]-phenyl}-amide

To a slurry of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (81 mg, 0.16 mmol, as prepared in Example 14, step (b)) in CH₂Cl₂(3 mL) was added NEt₃ (33 μL, 0.24 mmol). The solution was then treatedwith 2,2-dimethyl-[1,3]dioxan-5-one (31 mg, 0.24 mmol) and the reactionwas allowed to stir for 3 h. At this time NaBH(OAc)₃ (51 mg, 0.24 mmol)was added in one portion, and the reaction was allowed to stir for anadditional 4h. The reaction was diluted with H₂O (10 mL) and extractedwith EtOAc (2×25 mL). The organic extracts were dried (Na₂SO₄) andconcentrated in vacuo. Purification by silica gel preparative thin layerchromatography (10% MeOH—CHCl₃) afforded 22 mg (28%) of the titlecompound as an off-white semi-solid. Mass spectrum (ESI, m/z): Calcd.for C₂₈H₃₅N₅O₃, 490.2 (M+H). found 490.6.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-hydroxy-1-hydroxymethyl-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoro-acetic acid

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2,2-dimethyl-[1,3]dioxan-5-yl)-piperidin-4-yl]-phenyl}-amide(22 mg, 0.04 mmol, as prepared in the previous step) in THF—H₂O (1 mL,4:1 v/v) was added TFA (0.4 mL), and the reaction was allowed to stirfor 1 h. Removal of the solvent under vacuum afforded 14 mg (60%) of thetitle compound as an amber foam. ¹H-NMR (CD₃OD, 400 MHz): δ 1.78-1.90(m, 4H), 2.03-2.16 (m, 3H), 2.29 (br s, 4H), 2.88-2.96 (m, 1H),3.37-3.40 (m, 1H), 3.46-3.53 (m, 2H), 3.74-3.78 (m, 3H), 5.83 (s, 1H),7.13 (d, 1H, J=2.0 Hz), 7.22 (dd, 1H, J=2.0, 8.4 Hz), 8.03 (s, 1H), 8.17(d, 1H, J=8.4 Hz); Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₁N₅O₃,450.2 (M+H). found 450.2.

Example 7 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amide

To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringeand stirring was continued for 3 h. Concentration in vacuo afforded 122mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture ofmorpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol),4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) andPyBroP (93 mg, 0.19 mmol) in CH₂Cl₂ (4 mL) was added DIEA (51 μL, 0.29mmol) and the reaction was allowed to stir overnight. The reaction wasdiluted with CH₂Cl₂ (50 mL), washed with H₂O (2×25 mL), dried (Na₂SO₄)and concentrated in vacuo. Purification of the crude product by silicagel preparative TLC afforded 8.1 mg (12%) of the title compound as awhite solid. ¹H-NMR (CDCl₃; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m,4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (brs, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s,1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1 Hz),9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₄N₆O₃, 503.27(M+H). found 503.1.

Example 8 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl-propionyl)-piperidin-4-yl]-phenyl}-amide

To a flask containing 3-morpholin-4-yl-propionic acid potassium salt (94mg, 0.47 mmol, prepared from 3-morpholin-4-yl-propionic acid ethyl esterexactly as described in Example 7, 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (179 mg, 0.36 mmol, as prepared in Example 14 (b)), EDCI (83mg, 0.43 mmol), and HOBT (68 mg, 0.5 mmol) was added DMF (4 mL). To thestirred slurry was added DIEA (157 μL, 0.9 mmol) and the reaction wasallowed to stir overnight. The reaction was diluted with H₂O (10 mL) andextracted with EtOAc (2×25 mL). The combined organic extracts were dried(Na₂SO₄), concentrated in vacuo and the crude product was purified bysilica gel preparative TLC to afford 10.4 mg (6%) of the title compoundas a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 1.49-1.93 (m, 5H),2.22-2.31 (m, 3H), 2.52 (br s, 4H), 2.58-2.63 (m, 3H), 2.74-2.76 (m,4H), 3.10-3.17 (m, 2H), 3.72 (br s, 4H), 3.97-4.02 (m, 2H), 4.76-4.81(m, 2H), 5.81-5.82 (m, 1H), 6.81-6.82 (m, 1H), 6.99-7.00 (m, 1H),7.09-7.13 (m, 1H), 7.70 (s, 1H), 8.26 (d, 1H, J=8.2 Hz), 9.51 (s, 1H);Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₆N₆O₃, 517.28 M+H). found517.3.

Example 9 5-Cyano-furan-2-carboxylic acid[2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

a) 1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine

To a cooled (0° C.) solution of 1.00 g (4.55 mmol) of2-bromo-4-fluoronitrobenzene (Oakwood) in 12 mL of EtOH was added 1.52mL (13.7 mmol) of piperidine. The solution was stirred at 0° C. for 0.5h and then at 60° C. for 4 h. The mixture was concentrated in vacuo,dissolved in EtOAc (60 mL), washed with water (3×100 mL) and brine (100mL), and dried (Na₂SO₄). Concentration in vacuo and chromatography on a50-g silica SPE column with 1-3% MeOH-dichloromethane afforded 1.06 g(77%) of the title compound as a tannish yellow solid. Mass spectrum(ESI, m/z): Calcd. for C₁₁H₁₄BrN₃O₂, 300.0 (M+H, ⁷⁹Br). found 300.1.

b) 1-Methyl-4-(2′-methyl-6-nitro-biphenyl-3-yl)-piperazine

A mixture of 200 mg (0.666 mmol)1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in theprevious step), 136 mg (0.999 mmol) and 77.0 mg (0.0666 mmol) oftetrakis(triphenylphosphine)palladium (0) under Ar was added 4.0 mL ofdegassed dimethoxyethane (DME) and 400 μL (0.799 mmol) of 2.0 M aqNa₂CO₃. The mixture was heated with stirring under Ar at 80° C. for 14h. The cooled (RT) mixture was concentrated and chromatographed on a10-g silica SPE column with 1-5% MeOH in dichloromethane-hexane (1:1).The product fractions were treated with 80 mg of decolorizing carbon,filtered, concentrated, and then rechromatographed on a similar columnwith 1-3% EtOH-dichloromethane to afford 265 mg of the title compound asa yellow resin (75% purity by ¹H-NMR as a mixture withtriphenylphosphine) that was used in the following reaction withoutfurther purification: Mass spectrum (ESI, m/z): Calcd. for C₁₁H₂₁N₃O₃,312.2 (M+H). found 312.2.

c) 5-Cyano-furan-2-carboxylic acid[2′-methyl-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

A mixture of 140 mg (0.337 mmol based on 75% purity) of1-methyl-4-(2′-methyl-6-nitro-biphenyl-3-yl)-piperazine (as prepared inthe previous step) and 70 mg of 10% palladium on carbon (Degussa typeE101-NE/W, Aldrich, 50% by weight water) in 5 mL of THF was stirredvigorously under a balloon of hydrogen for 1 h. The mixture was filtered(Celite), washed with dichloromethane (2×2 mL), and the solution of theresulting aniline was placed under Ar and used immediately in thefollowing reaction.

Simultaneously to the above reduction, 55.4 mg (0.404 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL ofanh dichloromethane under a CaSO₄ drying tube was treated with 52.9 μL(0.606 mmol) of oxalyl chloride followed by 10 μL of anh DMF. Thesolution was stirred for 25 min and quickly concentrated in vacuo at20-25° C. The resulting 5-cyano-furan-2-carbonyl chloride was placedunder high vacuum for 2-3 min and then immediately placed under Ar,cooled to 0° C. in an ice bath, and treated with the aniline solutionproduced above followed by 141 μL (0.808 mmol) ofN,N-diisopropylethylamine (DIEA). After stirring for 30 min at RT, themixture was concentrated in vacuo, and the resulting residue waschromatographed on a 20-g silica SPE column with 2-10%EtOH-dichloromethane to give a yellow resin (which was crystallized fromEtOAc-hexane) to afford 17.2 mg (13%) of the pure title compound as ayellow solid along with 70.3 mg of impure title compound. The impurefraction was dissolved in 50 mL of EtOAc, washed with satd aq NaHCO₃-1MK₂CO₃ (1:1, 2×20 mL) and brine (20 mL), dried (Na₂SO₄) and concentratedto afford 43.4 mg (32%) additional title compound as a crystallineyellow solid (total yield 45%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.32 (d, 1H,J=9.0 Hz), 7.73 (br s, 1H), 7.34-7.54 (m, 3H), 7.25 (d, 1H, J=7.7 Hz),7.12, 7.14 (AB q, 2H, J=3.7 Hz), 7.01 (dd, 1H, J=9.0, 2.8 Hz), 3.25-3.27(m, 4H), 2.59-2.62 (m, 4H), 2.38 (s, 3H), and 2.15 (s, 3H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₂₄N₄O₃, 401.2 (M+H). found 401.1.

Example 10 5-Cyano-furan-2-carboxylic acid[2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

a) 1-(2′-Fluoro-6-nitro-biphenyl-3-yl)-4-methyl-piperazine

The procedure of Example 9, step (b) was followed using 75.0 mg (0.250mmol) 1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared inExample 9, step (a)), 136 mg (0.999 mmol) 2-fluorophenylboronic acid,26.8 mg (0.0232 mmol) of tetrakis(triphenylphosphine)palladium (0) and400 μL (0.799 mmol) of 2.0 M aq Na₂CO₃ in DME except the mixture washeated for 22 h. Chromatography on a 5-g silica SPE column with 1-5%MeOH in dichloromethane-hexane (1:1) afforded 95.0 mg of the titlecompound (76% purity by ¹H-NMR as a mixture with triphenylphosphine) asa yellow resin that was used in the following reaction without furtherpurification. Mass spectrum (ESI, m/z): Calcd. for C₁₇H₁₈FN₃O₃, 316.1(M+H). found 316.2.

b) 5-Cyano-furan-2-carboxylic acid[2′-fluoro-5-(4-methyl-piperazin-1-yl)-biphenyl-2-yl]-amide

The procedure of Example 9, step (c) was followed using 93.2 mg (0.225mmol based on 76% purity) of1-(2′-fluoro-6-nitro-biphenyl-3-yl)-4-methyl-piperazine (as prepared inthe previous step), 46 mg of 10% palladium on carbon, 37.0 mg (0.270mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 35.3μL (0.405 mmol) of oxalyl chloride, 5.0 μL of anh DMF, and 94.1 μL(0.540 mmol) of DIEA. Chromatography on a 5-g silica SPE column with1-4% MeOH-dichloromethane afforded 69.8 mg (77%) of the title compoundas a yellow resin. ¹H-NMR (CDCl₃; 400 MHz): δ 8.04 (d, 1H, J=9.0 Hz),7.93 (br s, 1H), 7.434-7.48 (m, 1H), 7.37 (td, 1H, J=7.5, 1.8 Hz),7.22-7.31 (m, 2H), 7.13, 7.18 (AB q, 2H, J=3.7 Hz), 7.02 (dd, 1H, J=9.0,2.9 Hz), 6.88 (d, 1H, J=2.9 Hz), 3.24-3.27 (m, 4H), 2.57-2.60 (m, 4H),and 2.36 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₁FN₄O₂,405.2 (M+H). found 405.2.

Example 11 5-Cyano-furan-2-carboxylic acid[2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

a) 1-(3-Cyclohex-1-enyl-4-nitro-phenyl)-4-methyl-piperazine

A mixture of 102 mg (0.340 mmol)1-(3-bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example9, step (a)), 59.7 mg (0.474 mmol) cyclohexen-1-ylboronic acid, 43.8 mg(0.0379 mmol) of tetrakis(triphenylphosphine)palladium (0) under Ar wastreated with 206 μL (0.412 mmol) of 2.0 M degassed aq Na₂CO₃, 0.6 mLdegassed anh toluene and 0.2 mL degassed anh EtOH and the mixture washeated at 100° C. for 21 h. After cooling to RT, the mixture was pouredinto EtOAc (10 mL), washed with brine (10 mL), dried (Na₂SO₄) andconcentrated in vacuo. Chromatography on a 5-g silica SPE column with1-3% EtOH in dichloromethane afforded 126 mg of the title compound (74%purity by RP-HPLC (C18 column) as a mixture with triphenylphosphine) asa yellow oil that was used in the following reaction without furtherpurification. Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₃N₃O₃, 302.2(M+H). found 302.2.

b) 5-Cyano-furan-2-carboxylic acid[2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide

To 122 mg (0.299 mmol based on 74% purity) of1-(3-cyclohex-1-enyl-4-nitro-phenyl)-4-methyl-piperazine (as prepared inthe previous step) in 5.0 mL of EtOH-water (2:1) was added 83.8 mg (1.50mmol) of iron powder and 160 mg (2.99 mmol) of NH₄Cl and the mixturerefluxed under Ar for 12 h. An additional 83.8 mg (1.50 mmol) of ironpowder was added, and the mixture was refluxed for 1 h. The mixture waspoured into EtOAc (12 mL), filtered (Celite), washed with EtOAc (2×4mL), concentrated in vacuo and dissolved in anh THF (4.0 mL). Theresulting aniline solution was placed under Ar and used immediately inthe following reaction. 61.6 mg (0.449 mmol) of5-cyanofuran-2-carboxylic acid (as prepared in Example 1) in 2.5 mL ofanh dichloromethane under a CaSO₄ drying tube was treated with 60.0 μL(0.688 mmol) of oxalyl chloride followed by 10 μL of anh DMF. Thesolution was stirred for 25 min and quickly concentrated in vacuo at20-25° C. The residue was placed under high vacuum for 2-3 min and thenimmediately placed under Ar, cooled to 0° C. in an ice bath and treatedwith the aniline solution produced above followed by 104 μL (0.598 mmol)of DIEA. After stirring 30 min at RT, the mixture was concentrated invacuo, dissolved in EtOAc (20 mL), washed with 1M K₂CO₃ (2×10 mL) andbrine (10 mL), dried (Na₂SO₄) and concentrated in vacuo. The resultingresidue was chromatographed on a 10-g silica SPE column with 1-4%MeOH-dichloromethane to give a yellow resin which was then crystallizedfrom Et₂O-hexane to afford 84.7 mg (72%) of the title compound as acrystalline yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.57 (br s, 1H),8.26 (d, 1H, J=9.0 Hz), 7.20, 7.23 (AB q, 2H, J=3.7 Hz), 6.86 (dd, 1H,J=9.0, 2.9 Hz), 6.74 (d, 1H, J=2.9 Hz), 5.84-5.85 (m, 1H), 3.20-3.22 (m,4H), 2.57-2.59 (m, 4H), 2.36 (s, 3H), 2.23-2.30 (m, 4H) and 1.79-1.84(m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₆N₄O₂, 391.2 (M+H).found 391.2.

Example 12 5-Cyano-furan-2-carboxylicacid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl-amide

a) 1-[3-(3,6-Dihydro-2H-pyran-4-yl)-4-nitro-phenyl]-4-methyl-piperazine

1-(3-Bromo-4-nitro-phenyl)-4-methyl-piperazine (as prepared in Example9, step (a)) (225.1 mg, 0.79 mmol), K₂CO₃ (310.9 mg, 2.25 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(Murata, M., et al, Synthesis, 778, (2000)) (157 mg, 0.75 mmol) indioxane (5 mL) was heated at 80° C. overnight under Ar. The reactionmixture was allowed to cool to RT, concentrated, and the resultingresidue was chromatographed on silica (10% EtOAc/hexane-20% MeOH/EtOAc)to obtain the title compound (82 mg, 36%). ¹H-NMR (CDCl₃; 400 MHz): δ8.04 (d, 1H, J=9.4 Hz), 6.78 (dd, 1H, J=9.4, 2.6 Hz), 6.58 (m, 1H, J=2.6Hz), 5.58 (m, 1H), 4.34 (m, 2H), 3.95 (t, 2H, J=5.3 Hz), 3.46 (m, 4H),2.57 (m, 4H), 2.38 (s, 3H), 2.30 (m, 2H).

b) 5-Cyano-furan-2-carboxylicacid[2-(3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl-amide

1-[3-(3,6-Dihydro-2H-pyran-4-yl)-4-nitro-phenyl]-4-methyl-piperazine (asprepared in previous step) (80 mg, 0.26 mmol) was converted to thecorresponding amine using a procedure similar to Example 4, step (d),and coupled with 5-cyano-furan-2-carbonyl chloride as prepared inExample 9, step (c) (obtained from 137 mg, 1.00 mmol of5-cyano-furan-2-carboxylic acid as prepared in Example 1) in CH₂Cl₂ (2mL) at 0° C. The product was isolated by flash chromatography on silica(50% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (62.2 mg,60%). ¹H-NMR (CDCl₃; 400 MHz): δ 8.35 (br s, 1H), 8.12 (d, 1H each,J=8.76 Hz), 7.24 (d, 1H, J=5.08 Hz), 7.19 (d, 1H, J=5.08 Hz), 6.88 (dd,1H, J=8.76, 2.7 Hz), 6.73 (d, 1H, J=2.7 Hz), 5.88 (br s, 1H), 4.34 (m,2H), 3.94 (t, 2H, J=5.3 Hz), 3.23 (m, 4H), 2.59 (m, 4H), 2.38 (br s,5H). LC-MS (ESI, m/z): Calcd. for C₂₂H₂₄N₄O₃, 393.1 (M+H). found 393.2.

Example 13 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a) 4-(4-Amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

The title compound was prepared by Suzuki coupling of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (Synthesis, 993, (1991)) according to the procedure inExample 35, step (b). Mass spectrum (ESI, m/z): Calcd. for C₁₆H₂₂N₂O₂,275.2 (M+H). found 275.1.

b) 4-(4-Amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-(4-amino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (0.35 g, 1.2 mmol) (as prepared in the previousstep) in methanol was hydrogenated over 10% Pd/C at 20 psi for 1 h. Thesolution was filtered and concentrated to give 0.35 g (100%) of thetitle compound as a yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₄N₂O₂, 277.2 (M+H). found 277.1.

c) 4-(4-Amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butylester

To a solution of 4-(4-amino-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (0.20 g, 0.71 mmol) (as prepared in the previous step)in DCM (3 mL) was added N-bromosuccinimide (NBS) (0.13 g, 0.71 mmol),and the reaction stirred at RT for 10 h. The reaction was diluted withEtOAc (10 mL) and washed with NaHCO₃ (2×10 mL) and brine (10 mL).Concentration of the organic layer gave 0.26 g (100%) of the titlecompound as a yellow foam. Mass spectrum (ESI, m/z): Calcd. forC₁₆H₂₃BrN₂O₂, 355.1 (M+H). found 355.1.

d) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester

A flask was charged with4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester(0.13 g, 0.36 mmol) (as prepared in the previous step), cyclohex-1-enylboronic acid (0.060 g, 0.48 mmol), Pd(PPh₃)₄ (0.04 g, 10 mol %), aqueous2M Na₂CO₃ (1.5 mL), ethanol (1.5 mL), and toluene (3 mL), and heated at80° C. for 3 h. The reaction was diluted EtOAc (10 mL), washed withNaHCO₃ (2×10 mL) and brine (10 mL), and the organic layer was dried overNa₂SO₄ and then concentrated. The title compound was eluted from a 20-gSPE cartridge (silica) with 30% EtOAc/hexane to give 0.10 g (85%) of thetitle compound as a yellow oil. Mass spectrum (ESI, m/z): Calcd. forC₂₂H₃₂N₂O₂, 357.2 (M+H). found 357.1.

e) 4-Cyano-1H-pyrrole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

A flask was charged with4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (0.050 g, 0.14 mmol) (as prepared in the previousstep), 4-cyano-1H-pyrrole-2-carboxylic acid (0.019 g, 0.14 mmol)(asprepared in Example 2), EDCI (0.040 g, 0.21 mmol), HOBt (0.019 g, 0.14mmol), DIEA (0.073 mL, 0.42 mmol), and DCM (0.5 mL) and stirred at 25°C. for 10 h. The reaction was loaded directly on a 10-g solid phaseextraction (SPE) cartridge (silica) and the resulting intermediate waseluted with 30% EtOAc/hexane. This compound was stirred at RT for 1 h in50% TFA/DCM (2 mL) and then concentrated and purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 12 min to give the titlecompound (0.052 g, 77%). ¹H-NMR (400 MHz, CD₃OD): δ 7.59 (s, 1H), 7.50(d, 1H), 7.22 (d, 1H), 7.16 (m, 2H), 5.74 (m, 1H), 3.54. (m, 2H), 3.16(m, 2H), 2.94 (m, 1H), 2.29 (m, 2H), 2.15 (m, 4H), 1.92 (m, 2H), 1.72(m, 4H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₆N₄O, 375.2 (M+H).found 375.1.

Example 14 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a)4-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (3.34 g, 10.9 mmol) (as prepared in Example 3, step (d))in 20 mL DCM was added DIEA (3.8 mL, 21.8 mmol) and PyBroP (5.6 g, 12.0mmol), and the reaction stirred at 25° C. for 15 min. A solution of4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (3.9 g, 10.9 mmol) (as prepared in Example 13, step(d)) in 10 mL DCM was added and the reaction stirred for 8 h at 25° C.The reaction was diluted EtOAc (60 mL) and washed with NaHCO₃ (2×60 mL)and brine (100 mL) and the organic layer was dried over Na₂SO₄ and thenconcentrated. The title compound was purified by flash chomatography(silica gel, 2% EtOAc/DCM) to give 5.5 g (85%) of the title compound asa yellow oil. Mass spectrum (ESI, m/z): Calcd. for C₃₃H₄₇N₅O₄Si, 606.2(M+H). found 606.2.

b) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (1.5 g, 2.5 mmol) (as prepared in the previousstep) in 10 mL of DCM and 0.3 mL EtOH was added 3 mL of TFA and thesolution stirred for 3 h at 25° C. The reaction was diluted with 5 mL ofEtOH and then concentrated. The residue was crystallized from methanoland ethyl ether to give 0.85 g (70%) of the title compound as a whitesolid. ¹H-NMR (400 MHz, CD₃OD) δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd,1H), 7.12 (d, 1H), 5.76 (m, 1H), 3.54. (m, 2H), 3.16 (m, 2H), 2.92 (m,1H), 2.30 (m, 4H), 2.10 (m, 2H), 1.75 (m, 6H). Mass spectrum (ESI, m/z):Calcd. for C₂₂H₂₅N₅O, 376.2 (M+H). found 376.2.

Example 15 4-Cyano-1H-pyrrole-2-carboxylic acid[4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amide

The title compound was prepared from 4-cyano-1H-pyrrole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in Example 13, step (e)) according to theprocedure in Example 37. ¹H-NMR (400 MHz, CDCl₃) δ 10.82 (s, 1H), 8.28(d, 1H), 8.18 (s, 1H), 7.48 (d, 1H), 7.16 (dd, 1H), 7.02 (s, 1H), 6.72(s, 1H), 5.88 (m, 1H), 4.82 (m, 1H), 3.98. (m, 1H), 3.20 (m, 1H), 2.70(m, 2H), 2.29 (m, 4H), 2.18 (s, 3H), 1.80 (m, 8H). Mass spectrum (ESI,m/z): Calcd. for C₂₅H₂₈N₄O₂, 417.2 (M+H). found 417.1.

Example 16 4-Cyano-1H-imidazole-2-carboxylic acid14-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl 1-amide

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in Example 13, step (b)) according to theprocedure in Example 37: ¹H-NMR (400 MHz, CDCl₃) δ 13.12 (br s, 1H),9.58 (s, 1H), 8.34 (d, 1H), 7.76 (s, 1H), 7.21 (dd, 1H), 7.05 (d, 1H),5.86 (s, 1H), 4.84 (m, 2H), 4.00 (m, 1H), 3.22 (m, 1H), 2.72 (m, 2H),2.30 (m, 4H), 2.21 (s, 3H), 1.80 (m, 8H). Mass spectrum (ESI, m/z):Calcd. for C₂₄H₂₇N₅O₂, 418.2 (M+H). found 418.1.

Example 17 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt

The title compound was prepared from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (d)) and4-[4-amino-3-(4-methyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (prepared according to the procedure in Example13, step (d), substituting 4-methyl-1-cyclohex-1-enyl boronic acid forcyclohex-1-enyl boronic acid) according to the procedure for Example 14:¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd, 1H),7.12 (d, 1H), 5.80 (m, 1H), 3.54. (m, 2H), 3.18 (m, 2H), 2.94 (m, 1H),2.30 (m, 3H), 2.12 (m, 2H), 1.92 (m, 5H), 1.54 (m, 1H), 1.12 (d, 3H).Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₇N₅O, 390.2 (M+H). found390.2.

Example 18 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

The title compound was prepared from4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (d)) and4-(4-amino-3-cyclopent-1-enyl-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (prepared according to the procedure in Example 13,step (d), substituting cyclopenten-1-yl boronic acid for cyclohex-1-enylboronic acid) according to the procedure for Example 14. ¹H-NMR (400MHz, DMSO-d₆) δ 14.25 (br s, 1H), 10.00 (s, 1H), 8.36 (s, 1H), 7.72 (d,1H), 7.18 (m, 2H), 6.06 (s, 1H), 4.12 (m, 1H), 3.42 (m, 2H), 3.18 (m,2H), 3.00 (m, 3H), 2.80 (m, 2H), 1.92 (m, 5H). Mass spectrum (ESI, m/z):Calcd. for C₂M₂₃N₅O, 362.2 (M+H). found 362.2.

Example 19

An alternate method for the synthesis of the intermediate described inExample 1 is described below.

5-Cyano-furan-2-carboxylic acid

A 250-mL, three-neck, round-bottom flask equipped with a mechanicalstirrer, a heating mantle, and a condenser was charged with5-formyl-2-furancarboxylic acid (9.18 g, 65.6 mmol) and pyridine (60mL). Hydroxylamine hydrochloride (5.01 g, 72.2 mmol) was added and themixture was heated to 85° C. Acetic anhydride (40 mL) was added and thereaction was stirred at 85° C. for 3 h, after which time the solvent wasevaporated at 40° C. under reduced pressure. The residue was dissolvedin water, basified with 2.0 N NaOH solution to pH 9, and extracted with4:1 dichloromethane/2-propanol until the pyridine was completely removed(5×200 mL). The aqueous solution was then acidified with 2.0 N HClsolution to pH 2, saturated with solid NaCl, and extracted with 4:1dichloromethane/2-propanol (5×200 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated in vacuo to dryness. The residuewas crystallized from dichloromethane to give 6.80 g of the titlecompound as a white solid (76%). Mass spectrum (ESI-neg, m/z) Calcd. forC₆H₃NO₃, 136.0 (M−H). found 136.1. The ¹H NMR spectrum was consistentwith the assigned structure.

Example 20 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-acetyl)-piperidin-4-yl]-phenyl}-amide

A flask was charged with methanesulfonyl-acetic acid (14 mg, 0.10 mmol),EDCI (30 mg, 0.15 mmol), HOBt (14 mg, 0.10 mmol), DIEA (36 μL, 0.20mmol) and 0.5 mL DCM and stirred at 25° C. After 10 min, a solutioncontaining 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (40 mg, 0.08mmol) (as prepared in Example 20, step (b)) and NEt₃ (14 μL, 0.09 mmol)in 0.5 mL DCM was added and the reaction allowed to proceed for 10 h at25° C. The reaction mixture was loaded on a 5-g SPE cartridge (silica)and the title compound was eluted with 10% EtOH/EtOAc to give 10 mg(25%) of a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 11.60 (br s, 1H),9.52 (s, 1H), 8.30 (d, 1H), 7.74 (s, 1H), 7.60 (dd, 1H), 7.03 (d, 1H),5.86 (m, 1H), 4.84 (m, 1H), 4.18 (s, 2H), 4.12 (m, 1H), 3.32 (m, 1H),3.20 (s, 3H), 2.82 (m, 2H), 2.30 (m, 4H), 1.98 (m, 2H), 1.84 (m, 5H),1.72 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₂₉N₅O₄S, 496.2(M+H). found 496.2.

Example 21 4-Cyano-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (88 mg, 0.18mmol) (as prepared in Example 14, step (b)), pyridine-2-carbaldehyde (17μL, 0.21 mmol), NEt₃ (30 μL, 0.21 mmol), sodium triacetoxyborohydride(56 mg, 0.25 mmol) and 0.8 mL of 1,2-dichloroethane and stirred for 10 hat 25° C. The solvent was evaporated, and the title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 20 min to give 81 mg (78%) of a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s,1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.88 (dd, 1H), 7.58 (d, 1H), 7.52 (m,1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 4.56 (s, 2H), 3.40 (m,2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.20 (m, 4H), 2.00 (m, 4H), 1.72 (m,4H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₀N₆O, 467.2 (M+H). found467.2.

Example 22 4-Cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2-ylmethyl-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

This compound was prepared according to the procedure in Example 21 from4-cyano-1H-imidazole-2-carboxylic acid[2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (asprepared in Example 17) and pyridine-2-carbaldehyde. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s,1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.52 (m,1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.74 (m, 1H), 4.56 (s, 2H), 3.40 (m,2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.48-2.22 (m, 3H), 2.18-2.06 (m, 4H),1.98-1.82 (m, 3H), 1.52 (m, 1H), 1.02 (s, 3H). Mass spectrum (ESI, m/z):Calcd. for C₂₈H₃₂N₆O, 481.2 (M+H). found 481.2.

Example 23 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol-2-ylmethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

This compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as preparedin Example 18) and 1-methyl-1H-imidazole-2-carbaldehyde according to theprocedure in Example 21. ¹H-NMR (400 MHz, CD₃OD): δ 8.03 (m, 2H), 7.50(d, 1H), 7.42 (s, 1H), 7.20 (m, 2H), 6.02 (m, 1H), 4.22 (s, 2H), 3.96(s, 3H), 3.30 (m, 2H), 2.82-2.40 (m, 7H), 2.13-1.84 (m, 6H). Massspectrum (ESI, m/z): Calcd. for C₂₆H₂₉N₇O, 456.2 (M+H). found 456.2.

Example 244-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid amide

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (51 mg, 0.10mmol) (as prepared in Example 14, step (b)), NEt₃ (22 μL, 0.15 mmol),trimethylsilyl isocyanate (16 μL, 0.11 mmol) and 1.0 mL of DCM andstirred for 10 h at 25° C. The solvent was evaporated and the titlecompound was purified by RP-HPLC (C18), eluting with 35-60% CH₃CN in0.1% TFA/H₂O over 11 min to give 30 mg (70%) of a white solid. ¹H-NMR(400 MHz, DMSO-d₆): δ 14.28 (br s, 1H), 9.76 (s, 1H), 8.34 (s, 1H), 7.84(d, 1H), 7.18 (dd, 1H), 7.08 (d, 1H), 6.00 (br s, 2H), 5.72 (m, 1H),4.18 (m, 2H), 2.80-2.60 (m, 3H), 2.24-2.10 (m, 4H), 1.80-1.60 (m, 6H),1.50 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₆N₆O, 419.2(M+H). found 419.0.

Example 25 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (75 mg, 0.15mmol) (as prepared in Example 14, step (b)), K₂CO₃ (84 mg, 0.60 mmol),2-fluoropyridine (27 μL, 0.30 mmol) and 0.3 mL of N,N-dimethylacetamideand stirred for 8 h at 120° C. The reaction was diluted with 3 mL of H₂Oand the title compound was purified by RP-HPLC (C18), eluting with30-50% CH₃CN in 0.1% TFA/H₂O over 9 min to give 50 mg (75%) of a whitesolid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.06 (m, 1H), 8.02 (s,1H), 7.94 (dd, 1H), 7.48 (d, 2H), 7.22 (dd, 1H), 7.12 (d, 1H), 6.98 (t,1H), 5.82 (m, 1H), 4.32 (m, 2H), 3.46 (m, 2H), 3.00 (m, 1H), 2.30 (m,4H), 2.18 (m, 2H), 1.96-1.74 (m, 6H). Mass spectrum (ESI, m/z): Calcd.for C₂₇H₂₈N₆O, 453.2 (M+H). found 453.2.

Example 26 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), and hydroxy-acetaldehyde according tothe procedure in Example 21. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H),8.02 (s, 1H), 7.22 (dd, 1H), 7.14 (d, 2H), 5.82 (m, 1H), 3.94 (m, 2H),3.74 (m, 2H), 3.30 (m, 2H), 3.18 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H),2.20-1.98 (m, 4H), 1.96-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₄H₂₉N₅O₂, 420.2 (M+H). found 420.2.

Example 27 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (77 mg, 0.16mmol) (as prepared in Example 14, step (b)), NEt₃ (24 μL, 0.16 mmol),acrylonitrile (12 μL, 0.18 mmol), 0.1 mL MeOH and 1.0 mL of1,2-dichloroethane and stirred for 1 h at 80° C. The reaction wasconcentrated and the title compound was purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 12 min to give 83 mg(95%) of a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.06(m, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 5.82 (m, 1H), 3.76 (m, 2H), 3.60(m, 2H), 3.28 (t, 2H), 3.12 (t, 2H), 2.92 (m, 1H), 2.30 (m, 4H),2.18-1.98 (m, 4H), 1.92-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₅H₂₈N₆O, 429.2 (M+H). found 429.2.

Example 28 4-Cyano-1H-imidazole-2-carboxylicacid[4-(1-carbamoylmethyl-piperidin-4-yl)-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (50 mg, 0.10mmol) (as prepared in Example 14, step (b)), NEt₃ (32 μL, 0.23 mmol),2-bromoacetamide (16 mg, 0.12 mmol), and 0.5 mL of DCM and stirred for 4h at 25° C. The reaction was concentrated and the title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 12 min to give 42 mg (75%) of a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 14.28 (br s, 1H), 9.78 (s, 1H), 9.50 (br s, 1H), 8.34 (s,1H), 8.00 (s, 1H), 7.88 (d, 1H), 7.72 (s, 1H), 7.18 (dd, 1H), 7.10 (d,1H), 5.76 (m, 1H), 3.94 (s, 2H), 3.58 (m, 2H), 3.12 (m, 2H), 2.80 (m,1H), 2.20 (m, 4H), 1.98 (m, 4H), 1.80 (m, 4H). Mass spectrum (ESI, m/z):Calcd. for C₂₄H₂₈N₆O₂, 433.2 (M+H). found 433.2.

Example 29 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (25 mg, 0.05mmol) (as prepared in Example 14, step (b)), pyridin-2-yl-acetic acidhydrochloride (10 mg, 0.06 mmol), EDCI (12 mg, 0.06 mmol), HOBt (8.0 mg,0.06 mmol), DIEA (36 μL, 0.20 mmol) and 0.2 mL DMF and stirred at 25° C.for 10 h. The reaction was diluted with 2 mL of H₂O and the titlecompound was purified by RP-HPLC (C18), eluting with 30-50% CH₃CN in0.1% TFA/H₂O over 9 min to give 22 mg (70%) of a white solid. ¹H-NMR(400 MHz, CD₃OD): δ 8.82 (d, 1H), 8.52 (t, 1H), 8.14 (d, 1H), 8.04 (s,1H), 7.96 (m, 3H), 7.20 (dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.68 (m,1H), 4.32 (m, 2H), 4.18 (m, 1H), 3.40 (m, 1H), 2.88 (m, 2H), 2.30 (m,4H), 2.06-1.60 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₀N₆O₂,495.2.2 (M+H). found 495.2.

Example 30 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using pyridin-3-yl-acetic acid. ¹H-NMR (400 MHz, CD₃OD): δ 8.80 (m,2H), 8.54 (d, 1H), 8.10 (d, 1H), 8.06 (t, 1H), 7.98 (s, 1H), 7.18 (dd,1H), 7.08 (d, 1H), 5.78 (m, 1H), 4.68 (m, 1H), 4.20 (m, 1H), 4.18 (s,2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.28 (m, 4H), 2.06-1.70 (m, 7H), 1.62(m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₉H₃₀N₆O₂, 495.2 (M+H).found 495.2.

Example 31 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using pyridin-4-yl-acetic acid. ¹H-NMR (400 MHz, CD₃OD): δ 8.78 (d,2H), 8.12 (d, 1H), 8.00 (m, 3H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.80 (m,1H), 4.66 (m, 1H), 4.22 (s, 2H), 4.18 (m, 1H), 3.34 (m, 1H), 2.84 (m,2H), 2.24 (m, 4H), 2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI,m/z): Calcd. for C₂₉H₃₀N₆O₂, 495.2 (M+H). found 495.2.

Example 32 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4-yl)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. ¹H-NMR (400 MHz,CD₃OD): δ 8.82 (s, 1H), 8.10 (d, 1H), 8.00 (s, 1H), 7.42 (s, 1H), 7.16(dd, 1H), 7.06 (d, 1H), 5.80 (m, 1H), 4.66 (m, 1H), 4.12 (m, 1H), 4.04(m, 2H), 3.92 (s, 3H), 3.28 (m, 1H), 2.82 (m, 2H), 2.26 (m, 4H),2.00-1.70 (m, 7H), 1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. forC₂₈H₃₁N₂O₂, 498.2 (M+H). found 498.2.

Example 33 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-1H-imidazol-4-yl-acetyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (asprepared in Example 14, step (b)), according to the procedure in Example29 using (1-methyl-1H-imidazol-4-yl)-acetic acid. ¹H-NMR (400 MHz,CD₃OD): δ 8.88 (s, 1H), 8.12 (d, 1H), 8.02 (s, 1H), 7.44 (s, 1H), 7.20(dd, 1H), 7.10 (d, 1H), 5.82 (m, 1H), 4.70 (m, 1H), 4.18 (m, 1H), 4.06(m, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.30 (m, 4H), 2.00-1.70 (m, 7H),1.64 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C₂₇H₂₉N₇O₂, 484.2(M+H). found 484.2.

Example 34 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amidedi-trifluoroacetic acid salt

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide

A flask was charged with4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (830 mg,1.34 mmol) (as prepared in Example 39, step (a)), K₂CO₃ (600 mg, 4.34mmol), sodium iodide (40 mg, 0.27 mmol), 4-(2-chloro-ethyl)-morpholinehydrochloride (260 mg, 1.40 mmol), and 5.0 mL of N,N-dimethylacetamideand stirred for 8 h at 80° C. The reaction was diluted with EtOAc (50mL) and washed with NaHCO₃ (2×50 mL), brine (50 mL) and concentrated.The title compound was purified by flash chomatography (silica gel, 5%MeOH/DCM) to give 650 mg (78%) of a white solid. Mass spectrum (ESI,m/z): Calcd. for C₃₄H₅₀N₆O₃Si, 619.4 (M+H). found 619.3.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid{2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-amide(650 mg, 1.05 mmol) (as prepared in the previous step) in 10 mL of DCMwas added 0.3 mL of EtOH and 3.0 mL of TFA, and the reaction was allowedto proceed for 2 h at 25° C. The reaction was diluted with 10 mL of EtOHand concentrated. The title compound was purified by RP-HPLC (C18),eluting with 30-50% CH₃CN in 0.1% TFA/H₂O over 9 min to give 600 mg(80%) of a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 8.18 (d, 1H), 8.04(s, 1H), 7.24 (dd, 1H), 7.14 (d, 1H), 5.84 (m, 1H), 3.84 (m, 4H), 3.76(m, 2H), 3.50 (m, 2H), 3.30-3.10 (m, 4H), 2.92 (m, 5H), 2.30 (m, 4H),2.20-2.00 (m, 4H), 1.90-1.74 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₈H₃₆N₆O₂, 489.2. found 489.2.

Example 35 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide

a) Trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester

A solution of tetrahydro-thiopyran-4-one (1.00 g, 8.61 mmol) in 10 ml ofTHF was added to a solution of LDA (2.0 M, 4.52 ml, 9.04 mmol) in 20 mlof THF at −78° C. under Ar. The mixture was warmed to RT and stirred for0.5 h, then cooled to −78° C. again. A solution ofN-phenyltrifluoromethanesulfonimide (3.42 g, 9.47 mmol) in 10 ml of THFwas added. The resulting mixture was warmed to RT and stirred for 0.5 hunder Ar. Treated with 200 ml of EtOAc, the mixture was washed with H₂O(3×50 mL), brine (50 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (hexane-3% EtOAc/hexane) gave 810 mg (38%) of the titlecompound as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.01 (m, 1H),3.30 (m, 2H), 2.86 (dd, 2H, J=5.7, 5.7 Hz), 2.58-2.64 (m, 2H). Massspectrum (ESI, m/z): Calcd. for C₆H₇F₃O₃S₂, 249.0 (M+H). found 249.3.

b) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-thiopyran

To a mixture of 4-nitrophenylboronic acid (418 mg, 2.50 mmol),trifluoro-methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (asprepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh₃)₄ (433 mg,0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of1,4-dioxane was added 2.0 M aq Na₂CO₃ solution (3.13 mL, 6.25 mmol). Theresulting mixture was stirred at 80° C. for 2 h and then cooled to RT.Treated with 200 mL of EtOAc, the mixture was washed with H₂O (2×30 mL),brine (30 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-3% EtOAc/hexane) gave 470 mg (85%) of the title compound as a lightbrown oil. ¹H-NMR (CDCl₃; 400 MHz): δ 8.19 (d, 2H, J=9.1 Hz), 7.48 (d,2H, J=9.1 Hz), 6.36 (m, 1H), 3.39 (m, 2H), 2.91 (t, 2H, J=5.7 Hz), 2.72(m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₁K₁NO₂S, 222.1 (M+H).found 222.3.

c) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide

A solution of 3-chloroperoxybenzoic acid (1.04 g, 4.62 mmol, 77%) in 15mL of dichloromethane (DCM) was added slowly to a solution of4-(4-nitro-phenyl)-3,6-dihydro-2H-thiopyran (as prepared in the previousstep, 465 mg, 2.10 mmol) in 15 mL of DCM at −78° C. under Ar. Themixture was stirred at −78° C. for 0.5 h, and then warmed to RT. Treatedwith 100 mL of EtOAc, the mixture was washed with 10% Na₂SO₃ (2×15 mL),satd aq NaHCO₃ solution (20 mL), H₂O (20 mL), brine (20 mL) and dried(Na₂SO₄). Removal of the solvent under reduced pressure followed byflash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave518 mg (97%) of the title compound as a white solid. ¹H-NMR (CDCl₃; 400MHz): δ 8.23 (d, 2H, J=9.0 Hz), 7.52 (d, 2H, J=9.0 Hz), 6.04 (m, 1H),3.86 (m, 2H), 3.26-3.31 (m, 2H), 3.18-3.23 (m, 2H).

d) 4-(1,1-Dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine

A mixture of 4-(4-nitro-phenyl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (asprepared in the previous step, 502 mg, 1.98 mmol) and 10% Pd/C (250 mg,50 wt %) in 15 mL of MeOH was stirred at RT under H₂ (balloon pressure)for 2 h. The Pd catalyst was removed by filtration on Celite, and thefiltrate was concentrated to give 314 mg (70%) of the title compound asa slightly yellow solid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.03 (d, 2H, J=8.3Hz), 6.67 (d, 2H, J=8.3 Hz), 3.51-3.79 (br s, 2H), 3.11-3.17 (m, 4H),2.70 (dddd, 1H, J=12.3, 12.3, 2.9, 2.9 Hz), 2.31-2.43 (m, 2H), 2.15-2.23(m, 2H).

e) 2-Bromo-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine

To a suspension of4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine (as prepared inthe previous step, 174 mg, 0.77 mmol) in 20 mL of 3:1 DCM/MeOH at 0° C.was added N-bromosuccinimide (NBS) (137 mg, 0.77 mmol) in 5 mL of DCMunder Ar. The mixture was warmed to RT and stirred for 1 h under Ar.Treated with 100 mL of EtOAc, the mixture was washed with H₂O (2×20 mL),brine (20 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(2-3% EtOAc/DCM) gave 155 mg (66%) of the title compound as a whitesolid. ¹H-NMR (CDCl₃; 400 MHz): δ 7.28 (d, 1H, J=2.0 Hz), 6.97 (dd, 1H,J=8.3, 2.0 Hz), 6.73 (d, 1H, J=8.3 Hz), 4.07 (br s, 2H), 3.09-3.14 (m,4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.26-2.39 (m, 2H),2.12-2.21 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₁H₁₄BrNO₂S,304.0 (M+H). found 304.1.

f)2-Cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine

To a mixture of2-bromo-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine (asprepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-ylboronic acid (70 mg, 0.542 mmol) and Pd(PPh₃)₄ (57 mg, 0.0493 mmol) in 5mL of 1,4-dioxane was added 2.0 M aq Na₂CO₃ solution (2.0 mL, 4.0 mmol).The resulting mixture was stirred at 80° C. for 8 h under Ar, and thencooled to RT. Treated with 50 mL of EtOAc, the mixture was washed withH₂O (3×15 mL), brine (20 mL) and dried (Na₂SO₄). Removal of the solventunder reduced pressure followed by flash chromatography of the residueon silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compoundas a brown solid. ¹H-NMR (CDCl₃; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74(br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73(m, 2H). Mass spectrum (ESI, m/z): Calcd. for C₁₇H₂₃NO₂S, 306.1 (M+H).found 306.1.

g) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a mixture of2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenylamine(as prepared in the previous step, 122 mg, 0.50 mmol), potassium4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate(as prepared in Example 3, step (d), 134 mg, 0.44 mmol) andbromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP) (205 mg,0.44 mmol) in 5 mL of DMF was added DIEA (209 μL, 1.20 mmol). Theresulting mixture was stirred at RT for 18 h under Ar, cooled to RT.Treated with 50 mL of EtOAc, the mixture was washed with H₂O (3×10 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(1-3% EtOAc/DCM) gave 161 mg (73%) of the title compound as a colorlessoil. ¹H-NMR (CDCl₃; 400 MHz): δ 9.69 (s, 1H), 8.29 (d, 1H, J=8.4 Hz),7.78 (s, 1H), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 7.04 (d, 1H, J=2.2 Hz), 5.95(s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.2 Hz), 3.11-3.20 (m, 4H), 2.77(dddd, 1H, J=12.1, 12.1, 3.2, 3.2 Hz), 2.35-2.47 (m, 2H), 2.17-2.33 (m,6H), 1.74-1.89 (m, 4H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H). Massspectrum (ESI, m/z): Calcd. for C₂₈H₃₈N₄O₄SSi, 555.2 (M+H). found 555.3.

h) 4-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid[2-cyclohex-1-enyl-4-(1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide(as prepared in the previous step, 145 mg, 0.261 mmol) in 6 mL of DCMwas added 0.20 mL of EtOH followed by 2 mL of TFA. The resultingsolution was stirred at RT for 3 h. Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gel(20-25% EtOAc/DCM) gave 83 mg (90%) of the title compound as a whitesolid. ¹H-NMR (CDCl₃; 400 MHz): δ 12.34 (s, 1H), 9.60 (s, 1H), 8.35 (d,1H, J=8.4 Hz), 7.75 (s, 1H), 7.30 (dd, 1H, J=8.4, 2.2

Hz), 7.08 (d, 1H, J=2.2 Hz), 5.86 (m, 1H), 3.11-3.23 (m, 4H), 2.80(dddd, 1H, J=12.2, 12.2, 2.8, 2.8 Hz), 2.40-2.57 (m, 2H), 2.17-2.35 (m,6H), 1.74-1.91 (m, 4H). Mass spectrum (ESI, m/z): Calcd. forC₂₂H₂₄N₄O₃S, 425.2 (M+H). found 425.6.

Example 36 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt

a) 2-(3,6-Dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane

A mixture of trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-ylester (as prepared in Example 35, step (a), 500 mg, 2.01 mmol),bis(neopentyl glycolato)diboron (478 mg, 2.11 mmol), Pd(dppf)Cl₂ (147mg, 0.20 mmol) and KOAc (592 mg, 6.03 mmol) in 8 mL of 1,4-dioxane wasstirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with50 mL of EtOAc, the mixture was washed with H₂O (2×10 mL), brine (10 mL)and dried (Na₂SO₄). Removal of the solvent under reduced pressurefollowed by flash chromatography of the residue on silica gel (0-5%EtOAc/DCM) gave 351 mg (82%) of the title compound as a colorless oil.¹H-NMR (CDCl₃; 400 MHz): δ 6.62 (m, 1H), 3.63 (s, 4H), 3.21 (m, 2H),2.68 (t, 2H, J=5.8 Hz), 2.37 (m, 2H), 0.96 (s, 6H). Mass spectrum (ESI,m/z): Calcd. for C₁₀H₁₇BO₂S, 213.1 (M+H). found 213.1.

b)4-[4-Amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acidtert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563mmol),2-(3,6-dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (asprepared in the previous step, 131 mg, 0.619 mmol) and Pd(PPh₃)₄ (65 mg,0.056 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na₂CO₃ solution(2.25 mL, 4.5 mmol). The resulting mixture was stirred at 80° C. for 7 hunder Ar, and then cooled to RT. Treated with 50 mL of EtOAc, themixture was washed with H₂O (3×15 mL), brine (20 mL) and dried (Na₂SO₄).Removal of the solvent under reduced pressure followed by flashchromatography of the residue on silica gel (15-30% EtOAc/hexane) gave141 mg (67%) of the title compound as a colorless oil. ¹H-NMR (CDCl₃;400 MHz): δ 6.91 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.65(d, 1H, J=8.2 Hz), 5.91 (m, 1H), 4.22 (br s, 2H), 3.66 (br s, 2H),3.29-3.31 (m, 2H), 2.87 (dd, 2H, J=5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56(m, 3H), 1.78 (d, 2H, J=12.6 Hz), 1.50-1.63 (m, 2H), 1.48 (s, 9H). Massspectrum (ESI, m/z): Calcd. for C₂₁H₃₀N₂O₂S, 375.2 (M+H). found 375.2.

c)4-[4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

To a mixture of4-[4-amino-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 45 mg, 0.12mmol), potassium4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate(as prepared in Example 3, step (d), 44 mg, 0.144 mmol) and PyBroP (67mg, 0.144 mmol) in 2 mL of DMF was added DIEA (42 μL, 0.24 mmol). Theresulting mixture was stirred at RT for 4 h under Ar. Treated with 30 mLof EtOAc, the mixture was washed with H₂O (3×10 mL), brine (10 mL) anddried (Na₂SO₄). Removal of the solvent under reduced pressure followedby flash chromatography of the residue on silica gel (1-2% EtOAc/DCM)gave 64 mg (85%) of the title compound as a light yellow oil. ¹H-NMR(CDCl₃; 400 MHz): δ 9.51 (s, 1H), 8.21 (d, 1H, J=8.5 Hz), 7.78 (s, 1H),7.16 (dd, 1H, J=8.5, 2.1 Hz), 7.02 (d, 1H, J=2.1 Hz), 6.00 (m, 1H), 5.92(s, 2H), 4.25 (br s, 2H), 3.66 (t, 2H, J=8.2), 3.42 (m, 2H), 2.93 (dd,2H, J=5.7, 5.7 Hz), 2.79 (m, 2H), 2.63 (dddd, 1H, J=12.3, 12.3, 3.3, 3.3Hz), 2.49-2.56 (m, 2H), 1.82 (d, 2H, J=12.8 Hz), 1.56-1.66 (m, 2H), 1.49(s, 9H), 0.97 (t, 2H, J=8.2 Hz), 0.00 (s, 9H).

d)4-[4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester

A solution of 3-chloroperoxybenzoic acid (91 mg, 0.404 mmol, 77%) in 1mL of DCM was added slowly to4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(3,6-dihydro-2H-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 120 mg, 0.192mmol) in 3 mL of DCM at −78° C. under Ar. The mixture was stirred at−78° C. for 15 min, and then warmed to RT. Treated with 40 mL of EtOAc,the mixture was washed with 15% Na₂SO₃ (5 mL), satd aq NaHCO₃ solution(2×10 mL), H₂O (10 mL), brine (10 mL) and dried (Na₂SO₄). Removal of thesolvent under reduced pressure followed by flash chromatography of theresidue on silica gel (2-10% EtOAc/DCM) gave 85 mg (67%) of the titlecompound as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 9.23 (s, 1H),8.03 (d, 1H, J=8.3 Hz), 7.80 (s, 1H), 7.21 (dd, 1H, J=8.3, 2.0 Hz), 7.06(d, 1H, J=2.0 Hz), 5.93 (s, 2H), 5.75 (t, 1H, J=4.1 Hz), 4.25 (br s,2H), 3.86 (br s, 2H), 3.66 (t, 2H, J=8.2 Hz), 3.29 (t, 2H, J=6.3 Hz),3.03 (t, 2H, J=5.4 Hz), 2.74-2.86 (m, 2H), 2.64 (dddd, 1H, J=12.3, 12.3,3.3, 3.3 Hz), 1.82 (d, 2H, J=12.3 Hz), 1.55-1.65 (m, 2H), 1.49 (s, 9H),0.98 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd.for C₃₂H₄₅N₅O₆SSi, 656.3 (M+H). found 656.7.

e) 4-Cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide,trifluoroacetic acid salt

To a solution of4-[4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 81 mg, 0.123mmol) in 6 mL of DCM was added 0.20 mL of EtOH followed by 2 mL of TFA.The resulting solution was stirred at RT for 3 h. Removal of the solventunder reduced pressure gave 64 mg (96%) of the title compound as a whitesolid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.02 (s, 1H), 7.78 (d, 1H, J=8.3 Hz),7.29 (dd, 1H, J=8.3, 2.0 Hz), 7.21 (d, 1H, J=2.0 Hz), 5.71 (t, 1H, J=4.2Hz), 3.83 (br s, 2H), 3.51 (d, 2H, J=12.4 Hz), 3.33 (t, 2H, J=6.0 Hz),3.15 (td, 2H, J=13.1, 2.6 Hz), 3.01 (m, 2H), 2.94 (dddd, 1H, J=12.2,12.2, 3.5, 3.5 Hz), 2.08 (d, 2H, J=12.9 Hz), 1.91 (m, 2H, J=13.3, 13.3,13.3, 3.8 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₁H₂₃N₅O₃S, 426.2(M+H). found 426.2.

Example 37 4-Cyano-1H-imidazole-2-carboxylicacid[4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-phenyl]-amide

To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid[2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amidetrifluoroacetic acid salt (as prepared in Example 36, step (e), 62 mg,0.115 mmol) in 4 mL of 1:1 DCM/DMF at RT was added DIEA (60 μL, 0.345mmol). The mixture was stirred for 5 min, then acetic anhydride (11 μL,0.121 mmol) was added slowly to the mixture, and the resulting mixturewas stirred at RT for 0.5 h. Treated with 40 mL of EtOAc, the mixturewas washed with H₂O (2×20 mL). The aqueous layers were extracted withEtOAc (4×10 mL). The combined organic layers were concentrated in vacuo.The residue was purified by flash chromatography on silica gel (1-4%MeOH/DCM) yielding 50.9 mg (95%) of the title compound as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 13.0 (s, 1H), 9.10 (s, 1H), 8.13 (d, 1H,J=8.4 Hz), 7.77 (d, 1H, J=2.3 Hz), 7.26 (dd, 1H, J=8.4, 2.0 Hz), 7.08(d, 1H, J=2.0 Hz), 5.77 (t, 1H, J=4.3 Hz), 4.84 (dt, 1H, J=13.3, 2.1Hz), 4.00 (dt, 1H, J=13.3, 2.1 Hz), 3.89 (br s, 2H), 3.31 (t, 2H, J=6.2Hz), 3.23 (td, 1H, J=13.2, 2.5 Hz), 3.02 (m, 2H), 2.77 (dddd, 1H,J=11.9, 11.9, 3.4, 3.4 Hz), 2.68 (ddd, 1H, J=12.6, 12.6, 2.9 Hz), 2.18(s, 3H), 1.70-1.97 (m, 4H). Mass spectrum (ESI, m/z): Calcd. forC₂₃H₂₅N₅O₄S, 468.2 (M+H). found 468.1.

Example 38 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-dimethylamino-acetyl)-piperidin-4-yl]-phenyl}-amide

A mixture of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 655 mg, 1.30 mmol) in DCM (15mL) was cooled to 0° C. and DIEA (0.92 mL, 5.2 mmol) was added.Dimethylaminoacetyl chloride hydrochloride (211 mg, 1.3 mol) was thenadded portion wise over 10 min. The reaction mixture was stirred at 0°C. for 30 min and allowed to warm to RT and stirred for 2 h. Solvent wasremoved in vacuo and the resulting residue was partitioned between brineand DCM. The organic layer was separated, dried (Na₂SO₄) andconcentrated. The residue obtained was purified on silica (5% MeOH: DCM)to obtain 432 mg (70%) of the title compound as a white solid. ¹H-NMR(CDCl₃; 400 MHz): δ 9.49 (s, 1H), 8.24 (d, 1H, J=2.3 Hz), 7.70 (s, 1H),7.12 (dd, 1H, J=8.4, 2.1 Hz), 7.01 (s, 1H), 5.82 (m, 1H), 4.75 (d, 1H,J=13.4 Hz), 4.13 (d, 1H, J=13.4 Hz), 3.57 (d, 1H, J=14.2 Hz), 3.18 (d,1H, J=14.2 Hz), 3.12 (td, 1H, J=13.3, 2.4 Hz), 2.73 (dddd, 1H, J=11.9,11.9, 3.8, 3.8 Hz), 2.65 (ddd, 1H, J=13.3, 13.3, 2.4 Hz), 2.40 (s, 6H),2.18-2.32 (m, 4H), 1.60-1.98 (m, 8H). Mass spectrum (ESI, m/z): Calcd.for C₂₆H₃₂N₆O₂, 461.3 (M+H). found 461.2.

Example 38b 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide

HPLC purification of Example 38a also afforded a small amount of4-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)-piperidin-4-yl]-phenyl}-amide.¹H-NMR (CD₃OD; 400 MHz): δ 8.02 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.07(dd, 1H, J=8.4 Hz, J=2.4 Hz), 6.98 (d, 1H, J=2.4 Hz), 5.73-5.68 (m, 1H),4.60-4.51 (m, 1H), 3.76-3.68 (m, 1H), 3.20-3.11 (m, 1H), 2.81-2.70 (m,2H), 2.67 (s, 3H), 2.22-2.13 (m, 4H), 1.88-1.66 (m, 6H), 1.66-1.46 (m,2H). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₀N₆O₂, 447.2 (M+H). found447.3.

Example 394-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

a) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, trifluoroaceticacid salt

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 14, step (a), 81 mg, 0.123mmol) in 18 mL of DCM was added 1 mL of EtOH followed by 5 mL of TFA at0° C. The resulting solution was stirred at RT for 0.5 h, treated with20 mL of EtOH followed by 20 mL of n-PrOH and 5 mL of H₂O, the mixturewas then concentrated under reduced pressure to give a slightly yellowsolid. Flash chromatography of the compound on silica gel (2-4%MeOH/DCM) gave 0.87 g (85%) of the title compound as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 9.70 (s, 1H), 9.66 (br s, 1H), 9.15 (br s,1H), 8.29 (d, 1H, J=8.3 Hz), 7.78 (s, 1H), 7.13 (dd, 1H, J=8.3, 2.2 Hz),7.03 (d, 1H, J=2.2 Hz), 5.95 (s, 2H), 5.83 (m, 1H), 3.66 (t, 2H, J=8.4Hz), 3.55 (d, 2H, J=12.3 Hz), 2.95-3.11 (m, 2H), 2.76 (m, 1H), 2.18-2.33(m, 4H), 1.99-2.15 (m, 4H), 1.82 (m, 4H), 0.97 (t, 2H, J=8.3 Hz), 0.00(s, 9H). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₉N₅O₂Si, 506.3 (M+H).found 506.1.

b)4-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

A solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt (as prepared in the previous step, 116 mg, 0.192 mmol) andDIEA (134 μL, 0.770 mmol) in 4 mL of DCM was added slowly to solution oftriphosgene (23 mg, 0.0768 mmol) in 4 mL of DCM at −78° C. under Ar. Themixture was stirred at −78° C. for 15 min, warmed to RT and stirred for15 min and cooled to −78° C. again. A suspension of 2-amino-ethanol (350μL, 5.77 mmol) in 4 mL of THF was added and the resulting mixture waswarmed to RT and stirred for 20 h under Ar. Treated with 100 mL ofEtOAc, the mixture was washed with H₂O (3×20 mL), brine (20 mL) anddried (Na₂SO₄). Removal of the solvent in vacuo followed by flashchromatography of the residue on silica gel (10% EtOAc/DCM then 5%MeOH/DCM) gave 95 mg (83%) of the title compound as a colorless oil.¹H-NMR (CDCl₃; 400 MHz): δ 9.68 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 7.77(s, 1H), 7.12 (dd, 1H, J=8.4, 2.2 Hz), 7.01 (d, 1H, J=2.2 Hz), 5.94 (s,2H), 5.83 (m, 1H), 4.96 (t, 1H, J=5.6 Hz), 4.11 (d, 2H, J=13.3 Hz), 3.75(ddd, 2H, J=4.4 Hz), 3.66 (t, 2H, J=8.3 Hz), 3.44 (ddd, 2H, J=5.0 Hz),3.36 (t, 1H, J=4.6 Hz), 2.91 (ddd, 2H, J=13.0, 2.2 Hz), 2.66 (dddd, 1H,J=12.2, 12.2, 3.3, 3.3 Hz), 2.18-2.33 (m, 4H), 1.75-1.91 (m, 6H), 1.67(dddd, 2H, J=12.9, 12.9, 12.9, 4.0 Hz), 0.97 (t, 2H, J=8.3 Hz), 0.00 (s,9H). Mass spectrum (ESI, m/z): Calcd. for C₃₁H₄₄N₆O₄Si, 593.3 (M+H).found 593.1.

c)4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid (2-hydroxy-ethyl)-amide (as prepared in the previous step, 95 mg,0.16 mmol) in 3 mL of DCM was added 0.10 mL of EtOH followed by 1.0 mLof TFA. The resulting solution was stirred at RT for 6 h. Removal of thesolvent under reduced pressure followed by flash chromatography of theresidue on silica gel (2-8% MeOH/DCM) gave 68 mg (92%) of the titlecompound as a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.09 (d, 1H, J=8.4Hz), 8.00 (s, 1H), 7.15 (dd, 1H, J=8.4, 2.2 Hz), 5.79 (m, 1H), 4.15 (dd,2H, J=13.3, 1.1 Hz), 3.61 (t, 2H, J=5.9 Hz), 3.27-3.32 (m, 2H), 2.90(ddd, 2H, J=13.0, 13.0, 2.5 Hz), 2.73 (dddd, 1H, J=12.1, 12.1, 2.6, 2.6Hz), 2.26 (m, 4H), 1.73-1.88 (m, 6H), 1.62 (dddd, 2H, J=12.6, 12.6,12.6, 4.0 Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₅H₃₀N₆O₃, 463.2(M+H). found 463.2.

Example 40 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide

a) Methanesulfonic acid 2-methanesulfonyl-ethyl ester

To a solution of methanesulfonyl chloride (484 mg, 4.23 mmol) in 15 mLof DCM at 0° C. was added 2-methanesulfonyl-ethanol (500 mg, 4.03 mmol)in 10 mL of DCM followed by DIEA (1.05 mL, 6.05 mmol) under Ar. Themixture was warmed to RT and stirred for 20 h under Ar. The mixture wastreated with 100 mL of EtOAc and washed with H₂O (3×20 mL), brine (20mL) and dried (Na₂SO₄). Removal of the solvent in vacuo gave 534 mg(66%) of the title compound as a brown oil. ¹H-NMR (CDCl₃; 400 MHz): δ4.67 (d, 2H, J=5.5 Hz), 3.46 (d, 2H, J=5.5 Hz), 3.11 (s, 3H), 3.04 (s,3H).

b) 4-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-amide

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 85 mg, 0.174 mmol) and DIEA(91 μL, 0.521 mmol) in 3 mL of DCM at RT was added 2-methanesulfonicacid 2-methanesulfonyl-ethyl ester (as prepared in the previous step, 42mg, 0.208 mmol). The resulting mixture was stirred at RT for 3 h.Treated with 50 mL of EtOAc, the mixture was washed with H₂O (2×20 mL),brine (10 mL) and dried (Na₂SO₄). Removal of the solvent in vacuofollowed by flash chromatography of the residue on silica gel (1-3%MeOH/DCM) gave 54 mg (65%) of the title compound as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 9.54 (s, 1H), 8.25 (d, 1H, J=8.4 Hz), 7.72(s, 1H), 7.15 (dd, 1H, J=8.4, 2.0 Hz), 7.04 (d, 1H, J=2.0 Hz), 5.85 (m,1H), 3.21 (t, 1H, J=6.5 Hz), 3.09 (s, 3H), 3.02-3.11 (m, 2H), 2.92 (t,2H, J=6.5 Hz), 2.52 (dddd, 1H, J=12.1, 12.1, 3.3, 3.3 Hz), 2.18-2.34 (m,4H), 2.18 (t, 2H, J=10.8 Hz), 1.64-1.94 (m, 8H). Mass spectrum (ESI,m/z): Calcd. for C₂₅H₃₁N₅O₃S, 482.2 (M+H). found 482.2.

The following compounds have been prepared according to the examples asindicated:

Mass Spectrum [M + H]⁺ Proc. Example Structure Calcd. Found Formula OfEx 41

497.2 497.2 C₂₈H₂₈N₆O₃ 29 42

497.2 497.3 C₂₈H₂₈N₆O₃ 29

Example 43 4-Cyano-1H-imidazole-2-carboxylicacid{2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-phenyl}-amide

A solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 75.0 mg, 0.15 mmol) in CH₂Cl₂(10 mL) was treated with Et₃N (64.1 μL, 0.46 mmol) and cooled to 0° C.The mixture was treated with nicotinoyl chloride hydrochloride (0.030 g,0.17 mmol) and stirred at 0° C. for 15 min then at room temperature for17 h. The reaction mixture was adsorbed directly onto silica gel. Silicagel chromatography (10% MeOH in EtOAc) afforded the title compound (61.0mg, 83%) as a white solid. ¹H-NMR (CDCl₃; 400 MHz): δ 9.51 (br s, 1H),8.77 (s, 1H), 8.70-8.66 (m, 1H), 8.32 (d, 1H, J=8.4 Hz), 7.86-7.81 (m,1H), 7.70 (s, 1H), 7.42-7.37 (m, 1H), 7.17 (d, 1H, J=8.4 Hz), 7.06-7.04(m, 1H), 5.87-5.82 (m, 1H), 4.98-4.87 (m, 1H), 3.94-3.84 (m, 1H),3.29-3.18 (m, 1H), 2.98-2.86 (m, 1H), 2.86-2.76 (m, 1H), 2.34-2.20 (m,4H), 1.94-1.72 (m, 9H). LC-MS (ESI, m/z): Calcd. for C₂₈H₂₈N₆O₂, 481.2(M+H). found 481.3.

Example 44 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt

a)[2-(4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester

A solution of N—BOC-glycine (0.29 g, 1.63 mmol) in CH₂Cl₂ (10 mL) wastreated with DIEA (0.85 mL, 4.90 mmol), HOBt (0.26 g, 1.96 mmol), andEDCI (0.38 g, 1.96 mmol). The mixture was stirred at room temperaturefor 10 min and added to a suspension of4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 0.80 g, 1.63 mmol) in CH₂Cl₂(20 mL). The solution was stirred at room temperature for 17 h. Solventswere evaporated in vacuo. Silica gel chromatography (50% EtOAc inhexanes) afforded the title compound (0.41 g, 47%) as a white solid.¹H-NMR (CDCl₃; 400 MHz): δ 9.53 (s, 1H), 8.26 (d, 1H, J=8.4 Hz),7.80-7.78 (m, 1H), 7.71 (s, 1H), 7.45-7.43 (m, 1H), 7.06 (d, 1H, J=8.4Hz), 7.00 (s, 1H), 5.83 (br s, 1H), 5.76 (br s, 1H), 4.78-4.68 (m, 1H),3.96-3.85 (m, 2H), 3.17-3.03 (m, 1H), 2.78-2.63 (m, 2H), 2.29 (br s,2H), 2.22 (br s, 2H), 1.95-1.87 (m, 2H), 1.86-1.72 (m, 4H), 1.70-1.55(m, 2H), 1.44 (s, 9H). LC-MS (ESI, m/z): Calcd. for C₂₉H₃₆N₆O₄ 533.3(M+H). found 532.9.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt

A solution of[2-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-2-oxo-ethyl]-carbamicacid tert-butyl ester (as prepared in the previous step, 0.41 g, 0.77mmol) in CH₂Cl₂ (20 mL) was treated with EtOH (0.2 mL) and TFA (6 mL).The mixture stirred at room temperature for 45 min, and the solventswere evaporated in vacuo. The crude material was used directly in thenext step. LC-MS (ESI, m/z): Calcd. for C₂₄H₂₈N₆O₂ 433.2 (M+H). found433.2.

c) 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt

A suspension of 4-cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-acetyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl]-amidetrifluoroacetic acid salt (as prepared in the previous step, 0.42 g,0.77 mmol) in CH₂Cl₂ (20 mL) was treated with Na(OAc)₃BH (0.33 g, 1.54mmol) and solid glyoxal (44.6 mg, 0.77 mmol). The mixture stirred atroom temperature for 1 h, and the solvent was evaporated in vacuo. Theresidue was taken up in MeOH and the solids filtered off, and thefiltrate was concentrated in vacuo. Reverse phase HPLC (C-18 column)(20% to 60% acetonitrile in water with 0.1% TFA over 30 min) affordedthe title compound (83 mg, 19% over two steps) as a white solid. ¹H-NMR(CD₃OD; 400 MHz): δ 8.16-8.09 (m, 1H), 8.05-8.01 (m, 1H), 7.22-7.15 (m,1H), 7.11-7.06 (m, 1H), 5.84-5.79 (m, 1H), 4.72-4.62 (m, 1H), 4.24-3.91(m, 2H), 3.89-3.80 (m, 2H), 3.28-3.18 (m, 2H), 2.92-2.79 (m, 2H), 2.28(br s, 4H), 1.98-1.89 (m, 2H), 1.89-1.76 (m, 4H), 1.76-1.57 (m, 2H).LC-MS (ESI, m/z): Calcd. for C₂₆H₃₂N₆O₃ 477.2 (M+H). found 477.2.

Example 45 4-Cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethyl)-methyl-amino-acetyl]-piperidin-4-yl}-phenyl)-amide trifluoroacetic acid salt

A solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)-acetyl]-piperidin-4-yl}-phenyl)-amidetrifluoroacetic acid salt (as prepared in Example 44, step (c), 50.0 mg,0.085 mmol) in MeOH (3 mL) was treated with Na(OAc)₃BH (39.5 mg, 0.19mmol) and 37% aqueous formaldehyde (8.2 μL, 0.10 mmol). The mixture wasstirred at room temperature for 5.5 h, and the solvents were removed invacuo. Reverse phase HPLC (C-18 column) (10% to 50% acetonitrile inwater with 0.1% TFA over 30 min) afforded the title compound (19.5 mg,47%) as a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.12 (d, 1H, J=8.4Hz), 8.02 (s, 1H), 7.19 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz),5.84-5.79 (m, 1H), 4.72-4.64 (m, 1H), 4.39-4.23 (m, 2H), 3.84-3.79 (m,1H), 3.31-3.21 (m, 1H), 3.03-2.94 (m, 6H), 2.92-2.80 (m, 2H), 2.32-2.24(m, 4H), 2.00-1.90 (m, 2H), 1.90-1.76 (m, 5H), 1.78-1.59 (m, 2H). LC-MS(ESI, m/z): Calcd. for C₂₂H₃₄N₆O₃ 491.3 (M+H). found 491.2.

Example 46 4-Cyano-1H-imidazole-2-carboxylicacid[4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amidetrifluoroacetic acid salt

a) 5-Trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of LDA (23.4 mL, 35.1 mmol, 1.5 M in cyclohex) in THF (50 mL)was cooled to −78° C. under Ar. The solution was treated with3-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.00 g, 25.1 mmol)as a solution in THF (15 mL) via drop wise addition and stirred for 15min. The mixture was treated with1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonimide(12.5 g, 35.1 mmol) as a solution in THF (40 mL). The mixture wasallowed to warm to room temperature and stir 2.5 h. The reaction wasquenched with saturated aqueous NaHCO₃, diluted with Et₂O, and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo. Silica gel chromatography (5% EtOAc in hexanes) afforded thetitle compound (2.45 g, 30%) as a colorless oil. ¹H-NMR (CDCl₃; 400MHz): δ 5.97-5.89 (m, 1H), 4.09-4.01 (m, 2H), 3.54-3.45 (m, 2H),2.36-2.26 (m, 2H), 1.48 (s, 9H). LC-MS (ESI, m/z): Calcd. forC₁₁H₁₆F₃NO₅S 332.1 (M+H). found 332.1.

b)5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

PdCl₂dppf (0.16 g, 0.22 mmol), KOAc (2.18 g, 22.2 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.07 g,8.13 mmol), and dppf (0.12 g, 0.22 mmol) were placed in a round-bottomedflask, and the flask was flushed with Ar. A degassed solution of5-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (as prepared in the previous step, 2.45 g, 7.40 mmol)in dioxane (70 mL) was added to the flask and heated to 80° C. for 16 h.The mixture was filtered through a glass-fritted funnel to remove thesolid KOAc, and the filtrate was concentrated in vacuo. Silica gelchromatography (5% EtOAc in hexanes) afforded the title compound (1.62g, 71%) as a colorless oil. ¹H-NMR (CDCl₃; 400 MHz): δ 6.69-6.60 (m,1H), 3.98 (br s, 2H), 3.49-3.42 (m, 2H), 2.24-2.16 (m, 2H), 1.47 (s,9H), 1.27 (s, 12H). LC-MS (ESI, m/z): Calcd. for C₁₈H₂₈BNO₄ 310.2 (M+H).found 311.0.

c) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester

The title compound was prepared by the Suzuki coupling procedure ofExample 35, step (b) using 4-nitrophenylboronic acid (167 mg, 1.00 mmol)and 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in Example 13, step (a), 295 mg, 1.00mmol). Silica gel chromatography (10% EtOAc in hexanes) afforded thetitle compound (273 mg, 90%) as an oil. ¹H-NMR (CDCl₃; 400 MHz): δ 8.19(d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 6.23 (m, 1H), 4.12 (m, 2H),3.66 (m, 2H), 2.54 (m, 2H), 1.49 (s, 9H).

d) 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-ethanone

A solution of 4-(4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 304 mg, 1.00mmol) in a 1:1 mixture of DCM/TFA (10 mL) was stirred at roomtemperature for 3 h and concentrated. The residue was dried in vacuoovernight, was taken up in CH₂Cl₂ (10 mL) and was cooled to 0° C. Tothis solution, Et₃N (280 μL, 2 mmol) was added drop wise, followed byacetic anhydride (102 μL, 1 mmol). The resulting mixture was stirred at0° C. for 1 h and allowed to warm to room temperature. The reactionmixture was washed with brine, and the organic layer was separated,dried and concentrated. The resulting product was reduced to obtain thetitle compound (143 mg, 65%) using a procedure similar to Example 4,step (d). ¹H-NMR (CDCl₃; 400 MHz): δ 6.97 (d, 2H, J=8.4 Hz), 6.64 (d,2H, J=8.4 Hz), 4.75 (m, 1H), 3.93 (m, 1H), 3.13 (m, 3H), 2.66 (m, 2H),2.12 (s, 3H), 1.84 (m, 2H), 1.57 (m, 2H).

e) 1-[4-(4-Amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone

A solution of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanone (asprepared in the previous step, 0.36 g, 1.66 mmol) in CH₂Cl₂ (10 mL) wascooled to −78° C. and treated with NBS (0.28 g, 1.58 mmol) as asuspension in CH₂Cl₂ (4 mL). The reaction was allowed to warm to roomtemperature and stir for 30 min. The reaction was diluted with CH₂Cl₂and washed with saturated aqueous NaHCO₃. The organic layer was driedover MgSO₄ and concentrated in vacuo. The crude material was useddirectly in the next reaction. LC-MS (ESI, m/z): Calcd. for C₁₃H₁₇BrN₂O297.1 (M+H). found 297.1.

f)5-[5-(1-Acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in Example 46, step (b), 0.62 g, 2.02mmol) and 1-[4-(4-amino-3-bromo-phenyl)-piperidin-1-yl]-ethanone (asprepared in the previous step, 0.20 g, 0.67 mmol) in toluene:EtOH (2:1,9 mL) was treated with 2.0 M aqueous Na₂CO₃ (2.7 mL, 5.38 mmol) and wasdegassed with sonication under Ar. The mixture was heated to 80° C.,treated with Pd(PPh₃)₄ (54 mg, 0.05 mmol), and stirred at 80° C. for 4.5h. The reaction was cooled to room temperature, diluted with EtOAc, andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated in vacuo to afford the title compound (0.25 g,93%) as an off-white solid. LC-MS (ESI, m/z): Calcd. for C₂₃H₃₃N₃O₃422.2 (M+Na). found 422.0.

g)5-(5-(1-Acetyl-piperidin-4-yl)-2-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester

A solution of5-[5-(1-acetyl-piperidin-4-yl)-2-amino-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 0.25 g, 0.63mmol) in CH₂Cl₂ was treated with PyBroP (0.44 g, 0.94 mmol) and4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 0.21 g, 0.69mmol). The resulting slurry was cooled to 0° C. and treated with DIEA(0.33 mL, 1.88 mmol). The ice bath was removed and the mixture stirredat room temperature for 18 h. The reaction was diluted with CH₂Cl₂ andwashed with saturated aqueous NaHCO₃. The organic layer was dried overMgSO₄ and concentrated in vacuo. Silica gel chromatography (25-45% EtOAcin hexanes then 100% EtOAc) afforded the title compound (399 mg, 98%) asa white solid. LC-MS (ESI, m/z): Calcd. for C₃₄H₄₈N₆O₅Si 649.4 (M+H).found 649.9.

h) 4-Cyano-1H-imizazole-2-carboxylicacid[4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amidetrifluoroacetic acid salt

A solution of5-(5-(1-acetyl-piperidin-4-yl)-2-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 0.40 g, 0.61mmol) in CH₂Cl₂ (20 mL) and EtOH (0.4 mL) was treated with TFA (3 mL).The solution was stirred at room temperature for 0.5 h. The solventswere evaporated in vacuo, and the residue was immediately taken up inEtOH (25 mL) and stored at 5° C. for 11 h. The solution was concentratedin vacuo, and the residue was taken up in CH₂Cl₂ (20 mL) and EtOH (0.4mL) then treated with TFA (6 mL). The reaction was stirred at roomtemperature for 2 h, and the solvents were evaporated in vacuo. Reversephase HPLC (C-18 column) (10 to 80% acetonitrile in water with 0.1% TFAover 30 min) afforded the title compound (56.9 mg, 22%) as a whitesolid. ¹H-NMR (CDCl₃; 400 MHz): δ 8.06 (s, 1H), 7.81 (d, 1H, J=8.4 Hz),7.32 (d, 1H, J=8.4 Hz), 7.22 (s, 1H), 6.10-6.03 (m, 1H), 4.74-4.64 (m,2H), 4.11-4.02 (m, 1H), 3.95 (s, 2H), 3.50-3.37 (m, 2H), 3.29-3.20 (m,1H), 2.93-2.82 (m, 1H), 2.80-2.69 (m, 1H), 2.62-2.53 (m, 2H), 2.16 (s,3H), 1.98-1.84 (m, 2H), 1.78-1.54 (m, 2H). LC-MS (ESI, m/z): Calcd. forC₂₃H₂₆N₆O₂ 419.2 (M+H). found 419.2.

Example 47(4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-aceticacid trifluoroacetic acid salt

A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (33 mg, 0.067mmol) (as prepared in Example 14, step (b)), t-butyl bromoacetate (10μL, 0.067 mmol), NEt₃ (20 μL, 0.135 mmol) and 0.25 mL of DCM and stirredfor 10 h at 25° C. The reaction mixture was loaded on a 5g SPE cartridge(silica) and 23 mg (70%) of(4-[4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl]-piperidin-1-yl)-aceticacid tert-butyl ester was eluted with 25% EtOAc/DCM. This compound wasdissolved in 1 mL of DCM and 20 μL of EtOH and 1 mL of TFA were addedand the reaction stirred for 3 h at 25° C. The title compound waspurified by RP-HPLC (C18), eluting with 30-50% CH₃CN in 0.1% TFA/H₂Oover 12 min to give 10 mg (40%) of a white solid. ¹H-NMR (400 MHz,CD₃OD): δ 8.16 (d, 1H), 8.02 (s, 1H), 7.22 (dd, 1H), 7.10 (d, 1H), 5.72(m, 1H), 4.04. (s, 2H), 3.76 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1H), 2.29(m, 4H), 2.10 (m, 4H), 1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd.for C₂₄H₂₇N₅O₃, 434.2 (M+H). found 434.2.

Example 48 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

a)[3-(4-{4-[(4-Cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-1,1-dimethyl-3-oxo-propyl]-carbamicacid tert-butyl ester

To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt (as prepared in Example 14, step (b), 40.0 mg, 0.0818 mmol),3-tert-butoxycarbonylamino-3-methyl-butyric acid (J. Med. Chem., 34(2),633-642, (1991), 21.4 mg, 0.0981 mmol) and PyBroP (55.0 mg, 0.0981 mmol)in dichloroethane (2 mL) was added DIEA (43 μL, 0.25 mmol) and theresulting mixture was stirred at RT for 1 day under Ar. The mixture wasdiluted with EtOAc (30 mL) and washed with H₂O (2×10 mL), brine (10 mL),dried over Na₂SO₄ and then concentrated in vacuo. The residue waspurified by flash chomatography (silica gel, 10-40% EtOAc/hexane) togive 33.0 mg (70%) of the title compound as a colorless oil. Massspectrum (ESI, m/z): Calcd. for C₃₂H₄₂N₆O₄, 575.3 (M+H). found 574.8.

b) 4-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

To a solution of[3-(4-{4-[(4-cyano-1H-imidazole-2-carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-1,1-dimethyl-3-oxo-propyl]-carbamicacid tert-butyl ester (33.0 mg, 0.0574 mmol) (as prepared in theprevious step) in 3 mL of DCM and 0.10 mL EtOH at 0° C. was added 1.0 mLof TFA, the mixture was warmed to RT and stirred for 3 h. The reactionwas diluted with 3 mL of n-PrOH and then concentrated in vacuo. Theresidue was purified by flash chomatography (silica gel, 3-8% MeOH/DCM)to give 33.5 mg (99%) of the title compound as a white solid. ¹H-NMR(400 MHz, CDCl₃): δ 13.3 (s, 1H), 9.52 (s, 1H), 8.57 (br s, 3H), 8.26(d, 1H, J=8.6 Hz), 7.69 (s, 1H), 7.02 (dd, 1H, J=8.6, 1.7 Hz), 6.98 (d,1H, J=1.7 Hz), 5.78 (m, 1H), 4.67 (br d, 1H, J=13.4 Hz), 3.88 (br d, 1H,J=13.4 Hz), 3.10 (m, 1H), 2.55-2.85 (m, 4H), 2.23 (m, 4H), 1.72-2.01 (m,8H), 1.50 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₂H₃₄N₆O₂,475.3 (M+H). found 475.1.

Example 49 4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroaceticacid salt

a) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester

To a suspension of NaH (60% dispersion) (200 mg, 5.00 mmol) in DMF (5mL) at 0° C., a solution of methyl-1H-1,2,4-triazolecarboxylate (635 mg,5.00 mmol) in DMF (5 mL) was added dropwise. The resulting suspensionwas stirred at the same temperature for 30 min and treated with SEMCl(0.90 mL, 5.0 mmol). The resulting solution was stirred at RT for 30 minand poured onto ice. The product was extracted with ether (3×20 mL). Theether layers were combined, dried (Na₂SO₄) and concentrated in vacuo.The residue obtained was chromatographed on silica (10% EtOAc/hexane) toobtain the title compound (530 mg, 41%). Mass spectrum (ESI, m/z):Calcd. for C₁₀H₁₉N₃O₃Si, 258.1 (M+H). found 258.2.

b)4-(3-Cyclohex-1-enyl-4-{[1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4-]triazole-3-carbonyl]-amino}-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester (as prepared in the previous step, 257 mg, 1.00 mmol)in EtOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added. The resultingsolution was stirred at RT for 20 min and concentrated in vacuo. Theresidue obtained was suspended in ether (10 mL) and sonicated for 5 min.The ether was then removed in vacuo and the resulting residue was driedfor 4 hr to obtain1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (273 mg, 97%) which was directly used in the nextstep without any further purification.

A mixture of1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (as prepared above, 28 mg, 0.10 mmol), DIEA (34 μL,0.20 mmol), 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg,0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirredat RT for 12 h. The reaction mixture was diluted with DCM (5 mL) andwashed with saturated aqueous NaHCO₃ (10 mL) and water (10 mL). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The product was chromatographed on silica (20-40% EtOAc/hexane) toobtain the title compound (31.9 mg, 55%). Mass spectrum (ESI, m/z):Calcd. for C₃₁H₄₇N₅O₄Si, 481.2 (M-BOC+2H). found. 481.2.

c) 4H-[1,2,4-]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroaceticacid salt

To a solution of4-(3-cyclohex-1-enyl-4-{[1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 81.9 mg, 0.140mmol) in DCM (0.4 mL) and EtOH (13 μL), was added TFA (0.13 mL). Theresulting solution was stirred at RT for 3 h and concentrated in vacuo.The residue obtained was dried under vacuum for 1 h, suspended in ether(10 mL) and sonicated for 5 min. The solid formed was collected bysuction filtration to obtain the title compound (56 mg, 68%). ¹H-NMR(CD₃OD; 400 MHz): δ 8.53 (br s, 1H), 8.20 (d, 1H, J=8.4 Hz), 7.21 (dd,1H, J=8.4, 2.1 Hz), 7.11 (d, 1H, J=2.1 Hz), 5.83 (br s, 1H), 3.45 (m,2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14 (m, 2H), and1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₀H₂₅N₅O, 352.4(M+H). found 352.2.

Example 50 5-Chloro-4H-[1,2,4]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

a)5-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester

To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylicacid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35mmol) in DMF (10 mL) was added dropwise. The resulting suspension wasstirred at the same temperature for 30 min and then treated with SEMCl(0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 minand poured onto ice. The mixture was extracted with ether (3×20 mL) andthe ether layers were combined, dried (Na₂SO₄) and concentrated invacuo. The residue obtained was chromatographed on silica (10%EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum(ESI, m/z): Calcd. for C₁₀H₁₈ClN₃O₃Si, 292.0 and 294.0 (M+H). found291.5 and 293.6.

b)4-(4-{[5-Chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylicacid methyl ester (as prepared in the previous step, 227 mg, 0.780 mmol)in EtOH (2 mL), 2 N KOH (0.4 mL, 0.8 mmol) was added. The resultingsolution was stirred at RT for 20 min and concentrated in vacuo. Theresidue obtained was suspended in ether (10 mL) and sonicated for 5 min.The ether was then removed and the resulting residue was dried in vacuofor 4 h to obtain4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]triazole-3-carboxylicacid potassium salt (223 mg, 91%) which was directly used in the nextstep without any further purification.

A mixture of4-(4-[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carboxylicacid potassium salt (as prepared above, 35 mg, 0.10 mmol), DIEA (34 μL,0.10 mmol), 4-(4-amino-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in Example 14, step (b), 35.6 mg,0.100 mmol) and PyBroP (69.9 mg, 0.150 mmol) in DCM (2 mL) was stirredat RT for 12 h. The reaction mixture was diluted with DCM (5 mL) andwashed with saturated aqueous NaHCO₃ (10 mL) and water (10 mL). Theorganic layer was separated, dried (Na₂SO₄) and concentrated in vacuo.The product was chromatographed on silica (20-40% EtOAc/hexane) toobtain the title compound (52 mg, 85%). ¹H-NMR (CDCl₃; 400 MHz): δ 9.60(s, 1H), 8.29 (d, 1H, J=8.4 Hz), 7.18 (dd, 1H, J=8.4, 2.2 Hz), 7.13 (d,1H, J=2.2 Hz), 5.99 (s, 2H), 5.84 (br s, 1H), 4.18-4.25 (m, 2H),3.72-3.76 (m, 2H), 2.58-2.67 (m, 2H), 2.51-2.64 (m, 1H), 2.18-2.33 (m,4H), 1.78-1.92 (m, 6H), 1.55-1.65 (m, 2H), 1.49 (s, 9H), 0.93-0.98 (m,2H), 0.10 (s, 9H).

c) 5-Chloro-1H-[1,2,4-]-triazole-3-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt

To a solution of4-(4-{[5-chloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-[1,2,4]-triazole-3-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 63.3 mg, 0.102mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). Afterstirring the resulting mixture at RT for 12 h, another 0.1 mL of TFA wasadded. The reaction mixture was stirred for an additional 5 h at RT, thesolvents were evaporated, and the title compound was purified by RP-HPLC(C18) eluting with 20-70% CH₃CN in 0.1% TFA/H₂O over 20 min to obtainthe title compound (30 mg, 58%). ¹H-NMR (CD₃OD; 400 MHz): δ 8.14 (d, 1H,J=8.4 Hz), 7.20 (dd, 1H, J=8.4, 2.1 Hz), 7.13 (d, 1H, J=2.1 Hz), 5.82(br s, 1H), 3.45 (m, 2H), 3.19 (m, 2H), 2.98 (m, 1H), 2.28 (m, 4H), 2.14(m, 2H), and 1.95-1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. forC₂₀H₂₄ClN₅O, 386.1 and 388.1 (M+H). found 386.2 and 388.1.

Example 51 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt, and 5-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt

a) Cis/trans 2,6-Dimethyl-4-oxo-piperidine-1-carboxylic acid tert-butylester

A solution of cis/trans-2,6-dimethylpiperidinone (Coll. Czech. Chem.Commun.: 31(11), 4432-41, (1966), 1.27 g, 10.0 mmol) in ether (100 mL)was treated with aq 1 N NaOH (11 mL, 11 mmol) and (BOC)₂O (2.18 g, 10.0mmol). The resulting mixture as stirred at RT for 48 hr. The ether layerwas separated, dried and concentrated. The residue was chromatographedon silica (10% EtOAc-hexane) to obtain the title compound (1.10 g, 50%):LC-MS (ESI, m/z): Calcd. for C₁₂H₂₁NO₃, 128.1 (M-BOC+2H). found 128.1.

b) 4-(4-Amino-phenyl)-cis/trans 2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester

A solution of cis/trans N-Boc-2,6-dimethylpiperidinone (as prepared inthe previous step, 1.14 g, 5.00 mmol) in THF (20 mL) was cooled to −78°C. and treated with LDA (1.5 M solution in cyclohex, THF andethylbenzene, 4.4 mL, 6.5 mmol) under Ar. The resulting mixture wasstirred at the same temperature for 30 min and treated withN-phenyltrifluoromethanesulfonimide (2.34 g, 6.55 mmol) in THF (20 mL).The reaction mixture was stirred for another 30 min and allowed to warmto RT. After 30 min. at RT the reaction mixture was concentrated invacuo and the residue was taken up in ether (20 mL) and washed with coldwater (2×10 mL). The ether layer was dried (Na₂SO₄) and concentrated toaffordedcis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (890 mg, 49%) which was directly used in nextstep.

The title compound was then prepared according to the Suzuki couplingprocedure of Example 35, step (b) using 4-aminophenylboronic acid (219mg, 1.00 mmol) andcis/trans-2,6-dimethyl-4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared above, 321 mg, 1.00 mmol). Silica gelchromatography (10-20% EtOAc/hexanes) afforded4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (172 mg, 57%): Mass spectrum (ESI, m/z): Calcd.for C₁₈H₂₆N₂O₂, 303.2 (M+H) found 303.1. A solution of4-(4-amino-phenyl)-2,6-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (as prepared above, 380 mg, 1.25 mmol) in MeOH (10mL) was hydrogenated over 10% Pd/C (190 mg) at 20 psi for 1 h. Thesolution was filtered through a pad of Celite and concentrated to givethe title compound (360 mg, 94%). Mass spectrum (ESI, m/z): Calcd. forC₁₈H₂₈N₂O₂, 305.2 (M+H). found 305.6.

c) 4-(4-Amino-3-cyclohex-1-enyl-phenyl)-cis/trans2,6-dimethyl-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-(4-amino-phenyl)-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (as prepared in previous step, 334 mg, 1.09 mmol)in DCM (10 mL) was added NBS (195 mg, 1.09 mmol) and the reactionmixture was stirred at RT for 12 h. The reaction mixture was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃ (10 mL) andwater (10 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo to obtain4-(4-amino-3-bromo-phenyl)-cis/trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (367 mg, 87%). Mass spectrum (ESI, m/z): Calcd.for C₁₈H₂₇BrN₂O₂, 327.0 and 329.0 (M-t-Bu+H). found 327.0 and 328.9.

The title compound was then prepared according to the Suzuki couplingprocedure of Example 12, step (d) using cyclohexan-1-enyl boronic acid(157 mg, 1.25 mmol) and4-(4-amino-3-bromo-phenyl)-2,6-dimethyl-piperidine-1-carboxylic acidtert-butyl ester (as prepared above, 382 mg, 1.00 mmol) andchromatographed on silica (20% EtOAc/hexanes) to afford 254 mg (66%).Mass spectrum (ESI, m/z): Calcd. for C₂₄H₃₆N₂O₂, 384.2 (M+H). found385.1.

d)4-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester; and4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 384 mg, 1.00mmol), DIEA (0.34 μL, 2.0 mmol),4-(4-amino-3-cyclohex-1-enyl-phenyl)-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (as prepared in the previous step, 384 mg, 1.00mmol) and PyBroP (699 mg, 1.50 mmol) in DCM (20 mL) was stirred at RTfor 12 h. The reaction mixture was diluted with DCM (10 mL) and washedwith saturated aqueous NaHCO₃ (10 mL) and water (10 mL). The organiclayer was separated, dried (Na₂SO₄) and concentrated in vacuo toobtained a mixture of the above two title compounds (321 mg, 50.7%). Themixture was chromatographed on silica (10-20% EtOAc/hexane) to obtainthe individual title compounds.

4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (31 mg). Mass spectrum (ESI, m/z): Calcd. forC₃₅H₅₁N₅O₄Si, 634.3 (M+H). found 634.1.

4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester contaminated with 10% of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester (290 mg). Mass spectrum (ESI, m/z): Calcd. forC₃₅H₅₁N₅O₄Si, 634.3 (M+H). found 634.1.

e) 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt and 5-cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt

The title compounds were prepared from 290 mg (0.457 mmol) of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-cis-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester and 31 mg (0.048 mmol) of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-trans-2,6-dimethyl-piperidine-1-carboxylicacid tert-butyl ester according to the procedure in Example 14, step(b).

5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(cis-2,6-dimethyl-piperidin-4-yl)-phenyl]-amide bistrifluoroacetic acid salt (93 mg, 32%): ¹H-NMR (CD₃OD; 400 MHz): δ 8.17(d, 1H, J=8.4 Hz), 8.03 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.11 (s, 1H),5.72 (br s, 1H), 3.87 (m, 1H), 3.78 (m, 1H), 3.45 (m, 1H), 3.23 (m, 1H),3.07 (m, 1H), 2.22 (m, 4H), 2.19 (m, 2H), 1.75-1.92 (m, 4H), 1.56 (m,3H), 1.37 (m, 6H). Mass spectrum, ESI, m/z): Calcd. for C₂₄H₂₉N₅O, 404.2(M+H). found 404.2.

5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(trans-2,6-dimethyl-piperidin-4-yl)-phenyl]-amidebis trifluoroacetic acid salt (17.3 mg, 56%). ¹H-NMR (CDCl₃; 400 MHz): δ13.9 (br s, 1H), 10.3 (br s, 1H), 9.98 (s, 1H), 8.41 (d, 1H, J=8.4 Hz),7.75 (br s, 1H), 7.26 (dd, 1H, J=8.4, 2.0 Hz), 7.15 (d, 1H, J=2 Hz),5.92 (br s, 1H), 4.12 (m, 1H), 3.59 (m, 1H), 3.1-3.3 (m, 4H), 2.25-2.42(m, 6H), 2.05-1.78 (m, 6H), 1.62 (d, 3H, J=7.1 Hz), 1.43 (d, 3H, J=6.3Hz). Mass spectrum (ESI, m/z): Calcd. for C₂₄H₂₉N₅O, 404.2 (M+H). found404.2.

Example 52 5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide

a) 5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)2,2-dimethyl-[1,3]dioxolane-4-carbonyl)-piperidin-4-yl]-phenyl}-amide

To a solution of methyl (R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate(0.16 mL, 1.0 mmol) in MeOH (2 mL), 2 N KOH (0.5 mL, 1 mmol) was added.The resulting solution was stirred at RT for 20 min and concentrated invacuo. The residue obtained was suspended in ether (10 mL) and sonicatedfor 5 min. The ether was then removed and the resulting residue wasdried in vacuo for 4 h to obtain(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid potassium salt (173mg, 94%) which was directly used in the next step without purification.

To a solution of 4-cyano-1H-imidazole-2-carboxylic acid(2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide, trifluoroacetic acidsalt (as prepared in Example 14, step (b), 40 mg, 0.08 mmol) in DCM (1.5mL) was added to a mixture of(R)-(+)-2,2-dimethyl-1,3-dioxalane-4-carboxylic acid potassium salt (asprepared above, 18 mg, 0.090 mmol), EDCI (18.8 mg, 0.0900 mmol), HOBt(13.2 mg, 0.0900 mmol) and DIEA (42 μL, 0.24 mmol). The resultingmixture was stirred at RT for 6 h. Water (10 mL) was added and DCM layerwas separated, dried (Na₂SO₄) and concentrated. The residue obtained waschromatographed on silica (2% MeOH/DCM) to obtain title compound (47 mg,97%). Mass spectrum (ESI, m/z): Calcd. for C₂₈H₃₃N₅O₄, 504.2 (M+H).found 503.9.

b) 5-Cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}-amide

To a solution of 5-cyano-1H-imidazole-2-carboxylic acid{2-cyclohex-1-enyl-4-[1-(R)-(2,2-dimethyl-[1,3]dioxolane-4-carbonyl)-piperidin-4-yl]-phenyl}-amide(as prepared in the previous step, 45 mg, 0.090 mmol) in MeOH (1 mL) wasadded aq 2 N HCl (2 mL). The resulting mixture was stirred at RT for 12hr. Solvents were removed in vacuo and the resulting residue was driedfor 4 h. The ether (10 mL) was added and sonicated for 5 min. The etherwas removed in vacuo and the residue was dried for 12 h to obtain thetitle compound (21.3 mg, 52%). ¹H-NMR (DMSO; 400 MHz): δ 14.1 (br s,1H), 9.85 (s, 1H), 8.32 (s, 1H), 7.92 (d, 1H, J=8.4 Hz), 7.18 (dd, 1H,J=8.4, 2.1 Hz), 7.13 (d, 1H, J=2.1 Hz), 5.72 (br s, 1H), 4.51 (m, 1H),4.33 (m, 1H), 4.15 (m, 1H), 3.55 (m, 1H), 3.43 (m, 1H), 3.08 (m, 1H),2.81 (m, 1H), 2.63 (m, 1H), 2.12-2.24 (m, 4H), 1.31-1.38 (m, 10H). massspectrum (ESI, m/z): Calcd. for C₂₅H₂₉N₅O₄, 464.2 (M+H). found 464.1.

Example 53 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

a) 4-(1-Methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine

A solution of N-methoxypiperidinone (J. Org. Chem., 26, 1867, (1961),650 mg, 5.00 mmol) in THF (20 mL)) was cooled to −78° C. and treatedwith LDA (1.5 M solution in cyclohex, THF and ethylbenzene, 4.3 mL, 6.4mmol) under Ar. The resulting mixture was stirred at same temperaturefor 30 min and treated with N-phenyltrifluoromethanesulfonimide (2.3 g,6.4 mmol) in THF (20 mL). The reaction mixture was stirred for another30 min and allowed to warm to RT. After 30 min at RT, the reactionmixture was concentrated in vacuo and the residue obtained was taken upin EtOAc (20 mL) and washed with cold water (2×10 mL). EtOAc layer wasdried (Na₂SO₄) and concentrated to afforded trifluoromethanesulfonicacid 1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl ester (980 mg, 71%) as awhite foam which was directly used in next step.

The title compound was then prepared according to Suzuki couplingprocedure of Example 35, step (b) using 4-aminophenylboronic acid (219mg, 1.00 mmol) and trifluoromethanesulfonic acid1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl ester (as prepared above, 261mg, 1.00 mmol). Silica gel chromatography (20-50% EtOAc/hexanes)afforded 60 mg (29%). Mass spectrum (ESI, m/z): Calcd. for C₁₂H₁₆N₂O,205.1 (M+H). found 205.2.

b) 2-Cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine

A solution of 4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine(as prepared in previous step) (40.8 mg, 0.200 mmol) in MeOH (5 mL) washydrogenated over 10% Pd/C (20.4 mg) at 20 psi for 1 h. The solution wasfiltered through a pad of Celite and concentrated to give4-(1-methoxy-piperidin-4-yl)-phenylamine (38 mg, 92%) which was directlyused in the next step without purification.

To a solution of 4-(1-methoxy-piperidin-4-yl)-phenylamine (as preparedabove, 42 mg, 0.20 mmol) in DCM (2 mL) was added NBS (36.2 mg, 0.20mmol) and the reaction mixture was stirred at RT for 12 h. The reactionmixture was diluted with DCM (10 mL) and washed with saturated aqueousNaHCO₃ (10 mL) and water (10 mL). The organic layer was separated, dried(Na₂SO₄) and concentrated in vacuo to obtain2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (43mg, 74.5%) which was used in the next step without purification.

The title compound was then prepared according to Suzuki couplingprocedure of Example 12, step (d) using cyclohex-1-enyl boronic acid(27.9 mg, 1.00 mmol) and2-bromo-4-(1-methoxy-1,2,3,6-tetrahydro-pyridin-4-yl)-phenylamine (asprepared above, 44 mg, 0.15 mmol) and chromatographed on silica (20-50%EtOAc/hexanes) afforded2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (33 mg, 74%).Mass spectrum, (ESI, m/z): Calcd. for C₁₈H₂₆N₂O, 287.2 (M+H). found286.8.

c) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide

A mixture of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid, potassium salt (as prepared in Example 3, step (d), 35.6 mg, 0.100mmol), DIEA (0.34 μL, 0.20 mmol),2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenylamine (as preparedin previous step, 28.6 mg, 0.1 mmol) and PyBroP (69.9 mg, 0.150 mmol) inDCM (2 mL) was stirred at RT for 12 h. The reaction mixture was dilutedwith DCM (10 mL) and washed with saturated aqueous NaHCO₃ (10 mL) andwater (10 mL). The organic layer was separated, dried (Na₂SO₄) andconcentrated in vacuo. The product was chromatographed on silica (20-40%EtOAc/hexane) to obtain the title compound (26 mg, 48%). Mass spectrum(ESI, m/z): Calcd. for C₂₉H₄₁N₅O₃Si, 536.3 (M+H). found 536.2.

d) 5-Cyano-1H-imidazole-2-carboxylic acid[2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amidetrifluoroacetic acid salt

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide (asprepared in previous step, 31 mg, 0.020 mmol) in DCM (0.5 mL) and EtOH(11 μL) was added TFA (0.1 mL). The resulting solution was stirred at RTfor 6 h. The reaction mixture was concentrated in vacuo and theresulting residue was dried for 1 h, suspended in ether (10 mL) andsonicated for 5 min. The solid formed was collected by suctionfiltration to obtain the title compound (17.3 mg, 58%). ¹H-NMR (DMSO;400 MHz): δ 9.70 (s, 1H), 8.30 (s, 1H), 7.83 (d, 1H, J=8.4 Hz), 7.14 (d,1H, J=8.4 Hz), 7.05 (s, 1H), 5.71 (br s, 1H), 3.30-3.55 (m, 5H),2.41-2.62 (m, 2H), 2.12-2.19 (m, 4H), 1.60-1.85 (m, 8H). Mass spectrum(ESI, m/z): Calcd. for C₂₃H₂₇N₅O₂, 406.2 (M+H). found 406.1.

Example 54 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

a) 5-Nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

A solution of 202 mg (0.994 mmol) 2-bromo-5-nitropyridine in 4 mL oftoluene and 2 mL of EtOH was treated with 338 mg (1.09 mmol)4-trifluoromethane-sulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert-butyl ester (Synthesis, 993, (1991)) and 1.49 mL (2.981 mmol) 2 Maqueous Na₂CO₃. The mixture was degassed via sonication, placed underargon, treated with 80.3 mg (0.00700 mmol) Pd(PPh₃)₄ and heated to 80°C. for 4 h. The mixture was diluted with EtOAc and washed with water.The organic layer was dried over MgSO₄ and concentrated in vacuo. Theresulting residue was chromatographed on a 50-g silica Varian MegaBondElut column with 10-25% EtOAc-hexane to afford 226 mg (75%) of the titlecompound as a light yellow solid: Mass spectrum (ESI, m/z): Calcd. forC₁₅H₁₉N₃O₄, 306.1 (M+H). found 305.7.

b) 5-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 226 mg (0.740 mmol)5-nitro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (as prepared in the previous step) in 15 mL MeOH wastreated with 110 mg 10% Pd/C (Degussa type E101-NE/W, Aldrich, 50% byweight water) and 1 atm H₂ at room temperature for 18 h. The mixture wasfiltered through Celite, and the filter cake was washed with MeOH.Concentration afforded 220 mg (107%) of the title compound as acolorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C₁₅H₂₃N₃O₂,278.2 (M+H). found 278.0.

c)5-Amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]-bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 220 mg (0.793 mmol)5-amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (as prepared in the previous step) in 10 mL CH₂Cl₂ wastreated with 134 mg (0.753 mmol) N-bromosuccinimide at room temperaturefor 20 min. The mixture was diluted with CH₂Cl₂ and washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andconcentrated in vacuo. Chromatography of the residue on a 50-g silicaVarian MegaBond Elut column with 10-35% EtOAc-hexanes afforded 209 mg(74%) of the title compound as a colorless glassy solid. ¹H-NMR (CDCl₃;400 MHz): δ 6.97 (d, 1H, J=8.0 Hz), 6.91 (d, 1H, J=8.0 Hz), 4.28-4.15(br s, 2H), 4.06-3.90 (m, 2H), 2.85-2.75 (m, 2H), 2.77-2.68 (m, 1H),1.92-1.83 (m, 2H), 1.68-1.54 (m, 2H), 1.47 (s, 9H).

d)5-Amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 209 mg (0.587 mmol)5-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 5 mL oftoluene and 2.5 mL of EtOH was treated with 99.3 mg (0.645 mmol)4,4-dicyclohex-1-enylboronic acid and 2.34 mL (4.69 mmol) 2 M aqueousNa₂CO₃. The mixture was degassed via sonication, placed under argon,treated with 47.4 mg (0.0410 mmol) Pd(PPh₃)₄, and heated to 80° C. for16 h. The mixture was diluted with EtOAc and washed with water. Theaqueous layer was extracted with additional EtOAc, and the combinedorganic layers were dried over MgSO₄ and concentrated in vacuo.Chromatography of the residue on a 50-g silica Varian MegaBond Elutcolumn with 25% EtOAc-hexanes afforded 150 mg (66%) of the titlecompound as a white foamy solid. Mass spectrum (ESI, m/z): Calcd. forC₂₃H₃₅N₃O₂, 386.3 (M+H). found 386.3.

e)5-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

A solution of 150 mg (0.389 mmol)5-amino-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 15 mL ofCH₂Cl₂ was treated with 131 mg (0.428 mmol) of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (as prepared in Example 3, step (b)), 272 mg (0.584 mmol)PyBroP, and 203 μL (1.17 mmol) DIEA at room temperature for 3 h. Themixture was diluted with CH₂Cl₂ and washed with saturated aqueousNaHCO₃. The organic layer was dried over MgSO₄ and concentrated invacuo. Chromatography of the residue on a 50-g silica Varian MegaBondElut column with 50% EtOAc-hexanes afforded 215 mg (87%) of the titlecompound as a white solid. Mass spectrum (ESI, m/z): Calcd. forC₃₄H₅₀N₆O₄Si, 635.4 (M+H). found 635.3.

f) 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A solution of 215 mg (0.339 mmol)5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-(4,4-dimethyl-cyclohex-1-enyl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (as prepared in the previous step) in 10 mL ofCH₂Cl₂ was treated with three drops MeOH and 3 mL TFA at roomtemperature for 4 h. MeOH (10 mL) was added and the solvents evaporatedin vacuo. Chromatography of the residue on a 50-g silica Varian MegaBondElut column with 10% MeOH—CH₂Cl₂ afforded 210 mg (97%) of the titlecompound as a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.59 (d, 1H, J=8.4Hz), 8.04 (s, 1H), 7.28 (d, 1H, J=8.4 Hz), 6.02-5.93 (m, 1H), 3.58-3.48(m, 2H), 3.32-3.03 (m, 3H), 2.54-2.42 (m, 2H), 2.23-2.02 (m, 6H), 1.11(s, 6H). Mass spectrum (ESI, m/z): Calcd. for C₂₃H₂₈N₆O, 405.2 (M+H).found 405.2.

Example 55 4-Cyano-1H-imidazole-2-carboxylic acid[1′-(2-dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A suspension of 20.9 mg (0.203 mmol) N,N-dimethylglycine in 4 mL CH₂Cl₂was treated with 49.8 mg (0.197 mmol)bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) and 75 μL (0.54mmol) Et₃N at room temperature for 1 h. The mixture was then treatedwith 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetate (as prepared in Example 54, step (f)) at roomtemperature for 18 h. The mixture was diluted with CH₂Cl₂ and washedwith water. The organic layer was dried over MgSO₄ and concentrated invacuo. The residue was purified by RP-HPLC (C18) with 10-80% CH₃CN in0.1% TFA/H₂O over 30 min to afford 34.9 mg (53%) of the title compoundas a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.38 (d, 1H, J=8.4 Hz),8.05 (s, 1H), 7.33 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H), 4.68 (d, 1H,J=15.2 Hz), 3.82 (d, 1H, J=15.2 Hz), 3.16-3.05 (m, 1H), 3.01-2.94 (m,6H), 2.52-2.40 (m, 2H), 2.39 (s, 6H), 2.17-2.10 (m, 2H), 2.09-1.87 (m,2H), 1.67-1.59 (m, 2H), 1.12 (s, 6H). Mass spectrum (ESI, m/z): Calcd.for C₂₇H₃₅N₇O₂, 490.3 (M+H). found 490.4.

Example 56 4-Cyano-1H-imidazole-2-carboxylic acid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexhydro-[2,4′]bipyridinyl-5-yl]-amidetrifluoroacetic acid salt

A solution of 70.0 mg (0.135 mmol) 4-cyano-1H-imidazole-2-carboxylicacid[6-(4,4-dimethyl-cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide(as prepared in Example 54, step (f)) in 10 mL of CH₂Cl₂ was treatedwith 32.7 mg (0.162 mmol) methanesulfonic acid 2-methanesulfonyl-ethylester (as prepared in Example 40, step (a)) and 70.5 μL (0.405 mmol)DIEA at room temperature for 6 h. The mixture was diluted with CH₂Cl₂and washed with water. The organic layer was dried over MgSO₄ andconcentrated in vacuo. The residue was purified by RP-HPLC (C18) with20-60% CH₃CN in 0.1% TFA/H₂O over 30 min to afford 48 mg (85%) of thetitle compound as a white solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.65 (d, 1H,J=8.4 Hz), 8.05 (s, 1H), 7.34 (d, 1H, J=8.4 Hz), 6.05-5.98 (m, 1H),3.85-3.66 (m, 6H), 3.29-3.21 (m, 2H), 3.20-3.01 (m, 1H), 3.14 (s, 3H),2.53-2.45 (m, 2H), 2.30-2.15 (m, 4H), 2.15-2.10 (m, 2H), 1.62 (t, 2H,J=6.4 Hz), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. forC₂₆H₃₄N₆O₃S, 511.2 (M+H). found 511.3.

Example 57 5-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

a){2-[4-(4-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamicacid tert-butyl ester

To a solution of4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylicacid tert-butyl ester (231 mg, 0.380 mmol) (as prepared in Example 14,step (a)) in 2.5 mL of DCM and 0.4 mL EtOH was added 700 μL of TFA andthe solution stirred for 3 h at 25° C. The reaction was diluted with 4mL of EtOH and then concentrated to give ca. a 2:1 mixture of5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt to starting material by ¹H-NMR and LC/MS which was used in thefollowing step without further purification. The mixture in 3 mL of DCMwas added to a solution of 2-tert-butoxycarbonylamino-2-methyl-propionicacid (53 mg, 0.70 mmol), DIEA (122 μL, 0.700 mmol) and PyBroP (144 mg,0.300 mmol) in 3 mL of DCM and the reaction was stirred at 25° C.overnight. The reaction was diluted with EtOAc (25 mL) and washed withsatd aq NaHCO₃ (1×25 mL) and brine (25 mL) and the organic layer wasdried over Na₂SO₄ and then concentrated. Purification of the residue bypreparative TLC (50% EtOAc-hexanes) afforded 40 mg (15%) of the titlecompound as a white solid. Mass Spectrum (ESI, m/z): Calcd. forC₃₇H₅₅N₆O₅Si, 691.3 (M+H). found 691.1.

b) 5-Cyano-1H-imidazole-2-carboxylic acid{4-[1-(2-amino-2-methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amidetrifluoroacetic acid salt

To a solution of{2-[4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidin-1-yl]-1,1-dimethyl-2-oxo-ethyl}-carbamicacid tert-butyl ester (40 mg, 0.050 mmol) in 2 mL of DCM and 20 μL ofEtOH was added 1.5 mL of TFA. The solution was stirred for 3 h at 25°C., diluted with 2 mL of EtOH and concentrated in vacuo. Trituration ofthe residue with ether afforded 8.4 mg (29%) of the title compound as awhite solid. ¹H-NMR (CD₃OD; 400 MHz): δ 8.10 (d, 1H, J=8.4 Hz), 8.00 (s,1H), 7.16 (d, 1H, J=8.4 Hz), 7.07 (s, 1H), 5.79 (s, 1H), 4.55-4.48 (m,1H), 3.30 (s, 6H), 2.89-2.87 (m, 2H), 2.40-2.25 (m, 4H), 1.96-1.93 (m,2H), 1.86-1.83 (m, 6H), 1.64-1.61 (m, 2H). Mass Spectrum (ESI, m/z):Calcd. for C₂₆H₃₃N₆O₂, 461.2 (M+H). found 461.3.

Example 58 5-Cyano-1H-imidazole-2-carboxylic acid[6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4″]bipyridinyl-5-yl]-amide

a)5-Amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

To a mixture of5-amino-6-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (331 mg, 0.93 mmol) (as prepared in Example 54,step (c)) and cyclohexen-1-yl boronic acid (141 mg, 1.11 mmol) in 5 mLof EtOH, 10 mL of toluene and 5 mL of 2 M Na₂CO₃, was added Pd(PPh₃)₄(107 mg, 0.0930 mmol) and the result was heated at 80° C. for 16 h. Thereaction was diluted with 100 mL of ether and 100 mL of brine and thelayers were separated. The organic layer was dried (Na₂SO₄) andconcentrated in vacuo. Purification of the residue by columnchromatography (silica gel, 30-60% ether-hexanes) afforded 248 mg (74%)the title compound as an light brown oil LC-MS (ESI, m/z): Calcd. forC₂₁H₃₂N₃O₂ (M+H), 358.2. found 358.1.

b)5-{[4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester

To a solution of4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylatepotassium salt (296 mg, 0.970 mmol) (as prepared in Example 3, step (d))in 8 mL DCM was added DIEA (291 μL, 1.72 mmol) and PyBroP (512 mg, 1.10mmol), and the reaction was stirred at 25° C. for 15 min. A solution of5-amino-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (233 mg, 0.65 mmol) (as prepared in the previousstep) in 4 mL DCM was added and the reaction stirred overnight at 25° C.The reaction was diluted with EtOAc (25 mL) and washed with NaHCO₃ (1×25mL) and brine (25 mL) and the organic layer was dried over Na₂SO₄ andthen concentrated. The residue was purified by flash chomatography(silica gel, 5% MeOH—CHCl₃) to afford 167 mg (40%) of the title compoundas a white solid. Mass Spectrum (ESI, m/z): Calcd. for C₃₂H₄₆N₆O₄Si,607.3 (M+H). found 607.3.

c) 5-Cyano-1H-imidazole-2-carboxylic acid(6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4″]bipyridinyl-5-yl)-amidetrifluoroacetic acid salt

The title compound was prepared from5-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-6-cyclohex-1-enyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (167 mg, 0.27 mmol) using a procedure similar toExample 14, step (b) to afford 57 mg (43%) of the title compound as awhite solid. LC-MS (ESI, m/z): Calcd. for C₂H₂₄N₆O, 377.2 (M+H). found377.2.

d) 5-Cyano-1H-imidazole-2-carboxylic acid[6-cyclohex-1-enyl-1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]-amide

To a slurry of 5-cyano-1H-imidazole-2-carboxylic acid(6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amidetrifluoroacetic acid salt (57 mg, 0.11 mmol) in 5 mL of DCM was addedDIEA (50.4 μL, 0.290 mmol) followed by 30.5 mg (0.150 mmol) ofmethanesulfonic acid 2-methanesulfonyl-ethyl ester (as prepared inExample 40, step (a)). The reaction was allowed to stir overnight,diluted with 20 mL of DCM, washed with satd aq NaHCO₃ (1×20 mL) anddried over Na₂SO₄. Purification by preparative TLC (silica gel, 40%EtOAc-hexanes) afforded 22.3 mg (40%) of the title compound as a whitesolid. ¹H-NMR (DMSO; 400 MHz): δ 10.02 (s, 1H), 8.24 (s, 1H), 8.11 (d,1H, J=8.4 Hz), 7.18 (d, 1H, J=8.4 Hz), 5.96 (s, 1H), 3.04 (s, 3H),3.02-2.99 (m, 3H), 2.73 (t, 2H, J=2.7 Hz), 2.39-2.37 (m, 2H), 2.11-2.05(m, 4H), 1.85-1.64 (m, 10H). Mass Spectrum (ESI, m/z): Calcd. forC₂₄H₃₁N₆O₃S, 483.2 (M+H). found 483.3.

Example 59

An alternate method for the synthesis of the intermediate described inExample 3 is described below.

4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

a) 1H-Imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, a condenser, and an addition funnel with anitrogen inlet was charged with 1H-imidazole-4-carboxaldehyde (Aldrich,1.10 kg, 11.5 mol) and pyridine (3.0 L, 3.0 mol). The reaction flask wascooled to 8° C. with an ice bath and hydroxylamine hydrochloride (871 g,12.5 mol) was added slowly in portions to maintain the internaltemperature below 30° C. The reaction was allowed to cool to ambienttemperature and stirred for 2 h at ambient temperature. The resultingthick yellow solution was heated to 80° C. with a heating mantle andacetic anhydride (2.04 L, 21.6 mol) was added dropwise over 200 min tomaintain the temperature below 110° C. during the addition. The reactionmixture was heated at 100° C. for 30 min, after which time it wasallowed to cool to ambient temperature and then further cooled in an icebath. The pH was adjusted to 8.0 (pH meter) by the addition of 25 wt %NaOH (5.5 L) at such a rate that the internal temperature was maintainedbelow 30° C. The reaction mixture was then transferred into a 22-Lseparatory funnel and extracted with ethyl acetate (6.0 L). The combinedorganic layer was washed with brine (2×4.0 L), dried over MgSO₄,filtered, and concentrated to dryness under reduced pressure at 35° C.to give the crude product as a yellow semisolid. The resulting semisolidwas suspended in toluene (3.0 L) and stirred for 1 h, after which timeit was filtered to give a light yellow solid, which was resuspended intoluene (3.0 L) and stirred for 1 h. The resulting slurry was filteredand the filter cake washed with toluene (2×500 mL) to give the titlecompound as a light yellow solid [870 g, 82%). The ¹H and ¹³C NMRspectra were consistent with the assigned structure.

b) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 1H-imidazole-4-carbonitrile (830 g, 8.91 mol, asprepared in the previous step), potassium carbonate (2.47 kg, 17.8 mol),and acetone (6.0 L). Agitation was initiated and the mixture was cooledto 10° C. with an ice bath. SEMCl (1.50 kg, 9.00 mol) was added throughthe addition funnel over 210 min to maintain the internal temperaturebelow 15° C. The reaction was then allowed to warm to ambienttemperature and stirred at ambient temperature overnight (20 h). Thereaction mixture was then cooled in an ice bath to 10° C. and quenchedby the slow addition of water (8.0 L) over 30 min to maintain theinternal temperature below 30° C. The resulting mixture was transferredto a 22-L separatory funnel and extracted with ethyl acetate (2×7.0 L).The combined organics were concentrated under reduced pressure at 35° C.to give the crude product as a dark brown oil, which was purifiedthrough a plug of silica gel (16.5×20 cm, 2.4 kg silica gel) using 2:1heptane/ethyl acetate (15 L) as eluent. The fractions containing theproduct were combined and concentrated under reduced pressure at 35° C.to afford a mixture of the title compounds as a light brown oil [1785 g,90%). The ¹H NMR spectrum was consistent with the assigned structure andindicated the presence of a 64:36 ratio of regioisomers.

c)2-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile

A 22-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and a condenser with a nitrogen inlet wascharged with a mixture of1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile and3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazole-4-carbonitrile [600 g,2.69 mol, as prepared in the previous step) and carbon tetrachloride(1.8 L). Agitation was initiated and the mixture was heated to 60° C. Atthis point N-bromosuccinimide (502 g, 2.82 mol) was added in severalportions over 30 min, which resulted in an exotherm to 74° C. Thereaction was allowed to cool to 60° C. and further stirred at 60° C. for1 h. The reaction was allowed to cool slowly to ambient temperature andthe resulting slurry was filtered and the filtrate washed with satdNaHCO₃ solution (4.0 L). The organics were passed through a plug ofsilica gel (8×15 cm, silica gel; 600 g) using 2:1 heptane/ethyl acetate(6.0 L) as eluent. The fractions containing the product (based on TLCanalysis) were combined and concentrated under reduced pressure to givea crystalline light yellow solid, which was then filtered and washedwith heptane (500 mL) to give the title compound as a crystalline whitesolid [593 g, 73%). The ¹H and ¹³C NMR spectra were consistent with theassigned structure and showed no evidence of the minor regioisomer.

d) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid ethyl ester

A 12-L, four-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile[390 g, 1.29 mol, as prepared in the previous step) and anhydroustetrahydrofuran (4.0 L). Agitation was initiated and the reactionmixture was cooled to −50° C. using a dry ice/acetone bath.Isopropylmagnesium chloride (2.0 M in THF, 760 mL, 1.52 mol) was addedthrough the addition funnel over 30 min to maintain the internaltemperature below −40° C. The reaction was stirred for a further 30 minat −43° C., after which time it was cooled to −78° C. Ethylchloroformate (210 mL, 2.20 mol) was added through the addition funnelover 10 min to maintain the internal temperature below −60° C. Thereaction was stirred for a further 40 min at −70° C., at which point thedry ice/acetone bath was removed and the reaction was allowed to warm toambient temperature over 1.5 h. The reaction mixture was cooled in anice bath to 0° C. and quenched by the slow addition of satd ammoniumchloride solution (1.8 L) at such a rate that the internal temperaturewas maintained below 10° C. The reaction mixture was transferred into a12-L separatory funnel, diluted with ethyl acetate (4.0 L), and thelayers were separated. The organic layer was washed with brine (2×2.0 L)and concentrated under reduced pressure at 35° C. to give a brown oil.The crude oil was dissolved in dichloromethane (300 mL) and purified bychromatography (15×22 cm, 1.5 kg of silica gel, 10:1 to 4:1heptane/ethyl acetate) to give a yellow oil, which was dissolved inEtOAc (100 mL), diluted with heptane (2.0 L), and stored in arefrigerator for 5 h. The resulting slurry was filtered to give thetitle compound as a crystalline white solid (141 g, 37%). The ¹H and ¹³CNMR spectra were consistent with the assigned structure.

e) 4-Cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylicacid potassium salt

A 5-L, three-neck, round-bottom flask equipped with a mechanicalstirrer, a temperature probe, and an addition funnel with a nitrogeninlet was charged with 5 [400 g, 1.35 mol) and ethanol (4.0 L).Agitation was initiated and a water bath was applied after all of thesolid had dissolved. A solution of 6 N KOH (214.0 mL, 1.29 mol) wasadded through the addition funnel over 15 min to maintain the internaltemperature below 25° C. and the reaction was stirred for 5 min at roomtemperature. The solution was then concentrated to dryness under reducedpressure at 20° C. to give a white solid. The resulting solid wassuspended in methyl t-butyl ether (MTBE, 4.0 L) and stirred for 30 min,after which time the slurry was filtered and the filter cake washed withMTBE (1.0 L) to give the title compound as a white solid, which wasfurther dried under vacuum at ambient temperature for 4 d [366 g, 89%).The ¹H NMR, ¹³C NMR, and mass spectra were consistent with the assignedstructure. Anal. Calcd for C₁₁H₁₆KN₃O₃Si: C, 43.25; H, 5.28; N, 13.76.Found: C, 42.77; H, 5.15; N, 13.37. Karl Fisher: 1.3% H₂O.

Biological Activity In Vitro Assays

The following representative in vitro assays were performed indetermining the C-KIT biological activity of the compounds of Formula I.They are given to illustrate the invention in a non-limiting fashion.

c-Kit Fluorescence Polarization Kinase Assay

The compounds of the present invention are also specific inhibitors ofc-Kit. Selection of preferred compounds of Formula I for use as c-Kitinhibitors was performed in the following manner using an in vitrokinase assay to measure inhibition of the isolated kinase domain of thehuman c-kit receptor in a fluorescence polarization (FP) protocol. Thec-kit assay utilized the fluorescein-labeled phosphopeptide and theanti-phosphotyrosine antibody included in the Panvera Phospho-TyrosineKinase Kit (Green) supplied by Invitrogen. When c-kit phosphorylated thepoly Glu₄Tyr, the fluorescein-labeled phosphopeptide was displaced fromthe anti-phosphotyrosine antibody by the phosphorylated poly Glu₄Tyr,thus decreasing the FP value. The c-kit kinase reaction was incubated atroom temperature for 45 minutes under the following conditions: 1 nMc-kit (ProQinase, lot SP005), 100 ug/mL poly Glu₄Tyr, 50 uM ATP, 5 mMMgCl₂ 1 mM DTT, 0.01% Tween-20, 1% DMSO or compound in 100 nM Hepes, pH7.5. The kinase reaction was stopped with the addition of EDTA. Thefluorescein-labeled phosphopeptide and the anti-phosphotyrosine antibodywere added and incubated for 30 minutes at room temperature andfluorescence polarization was read. Data points were an average oftriplicate samples Inhibition and IC₅₀ data analysis were done withGraphPad Prism using a non-linear regression fit with a multiparamater,sigmoidal dose-response (variable slope) equation. The IC₅₀ for kinaseinhibition represents the dose of a compound that resulted in a 50%inhibition of kinase activity compared to DMSO vehicle control.

c-Kit BR-1 Assay

BR-1 cells are a dog mastocytoma line that expresses aconstitutive-active mutant KIT (Ma Y., B. J. Longley, X. Wang, J. L.Blount, K. Langley, G. H. Caughey. Clustering of activating mutations inc-kit's juxtamembrane coding region in canine mast cell neoplasms. JInvest Dermatol 112: 165-170, 1999.). Proliferation of BR-1 cells can beinhibited by KIT inhibitors, and a good relationship exists betweencompound potency in KIT enzyme assays and inhibition of BR-1proliferation. To assay inhibition of BR-1 cell proliferation, BR-1cells are suspended (1 million cells/ml) in DMEM (Delbeccio's ModifiedEagle's Media) containing 10% FCS, and 100 μl/well are plated intoclear-bottomed 96 well culture plates (CoStar 3610) containing 50 μA ofthe same media supplemented with serial dilutions of test compounds.Immediately following plating (time zero), 6 wells containing cells aretreated with 100 μl of Promega Cell TiterGlo reagent and incubated 10min with shaking. The intensity of the Cell TiterGlo signal (1 sec/well)is determined using a luminometer. The remaining cells are cultured 72hours (37° C. and 5% CO₂). Following the 72-hour growth interval, 100 μlof Promega Cell TiterGlo reagent is added to each well. The plates areincubated an additional 10 minutes with shaking and the intensity of theCell TiterGlo signal (1 sec/well) is determined using a luminometer.Cell proliferation is defined by the difference between the time zeroand time 72 hour signals. IC₅₀ values of test compounds are calculatedas the concentrations resulting in 50% inhibition of growth.

Biological Data Biological Data for C-KIT

The activity of selected compounds of the present invention is presentedbelow. All activities are in μM and have the following uncertainties:C-KIT kinase: +10%.

C-KIT C-KIT Com- Fluorescence BR-1 Pro- pound Polarization liferationNumber Name IC50 (μM) IC50 (μM)  4 5-Cyano-furan-2-carboxylic acid ND ND[4-(4-methyl-piperazin-1-yl)-2-(3- methyl-thiophen-2-yl)-phenyl]- amide 5 5-Cyano-furan-2-carboxylic acid ND ND[4-(4-methyl-piperazin-1-yl)-2-(4- methyl-thiophen-3-yl)-phenyl]- amide 6 4-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-hydroxy-1- hydroxymethyl-ethyl)-piperidin-4-  74-Cyano-1H-imidazole-2- ND ND carboxylic acid {2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl- acetyl)-piperidin-4-yl]-phenyl}-  84-Cyano-1H-imidazole-2- 0.042 ND carboxylic acid {2-cyclohex-1-enyl-4-[1-(3-morpholin-4-yl- propionyl)-piperidin-4-yl]-phenyl}-  95-Cyano-furan-2-carboxylic acid ND ND[2′-methyl-5-(4-methyl-piperazin-1- yl)-biphenyl-2-yl]-amide 105-Cyano-furan-2-carboxylic acid ND ND[2′-fluoro-5-(4-methyl-piperazin-1- yl)-biphenyl-2-yl]-amide 115-Cyano-furan-2-carboxylic acid 0.15 ND [2-cyclohex-1-enyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amide 12 5-Cyano-furan-2-carboxylicacid[2- >0.25 ND (3,6-dihydro-2H-pyran-4-yl)-4-(4-methyl-piperazin-1-yl)-phenyl- amide 13 4-Cyano-1H-pyrrole-2-carboxylic0.26 ND acid (2-cyclohex-1-enyl-4- piperidin-4-yl-phenyl)-amidetrifluoroacetic acid salt 14 4-Cyano-1H-imidazole-2- 0.071 ND carboxylicacid (2-cyclohex-1-enyl- 4-piperidin-4-yl-phenyl)-amide trifluoroaceticacid salt 15 4-Cyano-1H-pyrrole-2-carboxylic ND ND acid[4-(1-acetyl-piperidin-4-yl)-2- cyclohex-1-enyl-phenyl]-amide 164-Cyano-1H-imidazole-2- 0.057 ND carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-cyclohex-1-enyl- phenyl]-amide 174-Cyano-1H-imidazole-2- ND ND carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl- phenyl]-amide trifluoroacetic acid 184-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclopent-1-enyl-4-piperidin-4-yl-phenyl)- amide trifluoroacetic acid salt 204-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl- acetyl)-piperidin-4-yl]-phenyl}- 214-Cyano-1H-imidazole-2- 0.05 ND carboxylic acid [2-cyclohex-1-enyl-4-(1-pyridin-2-ylmethyl-piperidin- 4-yl)-phenyl]-amide trifluoroacetic22 4-Cyano-1H-imidazole-2- ND ND carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-(1-pyridin-2- ylmethyl-piperidin-4-yl)-phenyl]- 234-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclopent-1-enyl-4-[1-(1-methyl-1H-imidazol- 2-ylmethyl)-piperidin-4-yl]- 244-{4-[(4-Cyano-1H-imidazole-2- ND ND carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1- carboxylic acid amide 254-Cyano-1H-imidazole-2- ND ND carboxylic acid [2-cyclohex-1-enyl-4-(3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-4-yl)-phenyl]- 264-Cyano-1H-imidazole-2- 0.026 ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-hydroxy-ethyl)- piperidin-4-yl]-phenyl}-amide 274-Cyano-1H-imidazole-2- 0.080 ND carboxylic acid (4-[1-(2-cyano-ethyl)-piperidin-4-yl]-2-cyclohex-1- enyl-phenyl}-amide trifluoroacetic28 4-Cyano-1H-imidazole-2- ND ND carboxylic acid [4-(1-carbamoylmethyl-piperidin-4-yl)-2- cyclohex-1-enyl-phenyl]-amide 294-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-pyridin-2-yl-acetyl)- piperidin-4-yl]-phenyl}-amide 304-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-pyridin-3-yl-acetyl)- piperidin-4-yl]-phenyl}-amide 314-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-pyridin-4-yl-acetyl)- piperidin-4-yl]-phenyl}-amide 324-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(1-methyl-1H-imidazol-4- yl)-acetyl]-piperidin-4-yl}-phenyl)- 334-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-1H-imidazol-4-yl- acetyl)-piperidin-4-yl]-phenyl}- 344-Cyano-1H-imidazole-2- 0.052 ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-morpholin-4-yl-ethyl)- piperidin-4-yl]-phenyl}-amide di- 354-Cyano-1H-imidazole-2- 0.073 ND carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ⁶-thiopyran-4- yl)-4-piperidin-4-yl-phenyl]-amide36 4-Cyano-1H-imidazole-2- ND ND carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahy dro-1λ⁶-thiopyran-4- yl)-4-piperidin-4-yl-phenyl]-amide37 4-Cyano-1H-imidazole-2- >0.25 ND carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,1-dioxo- 1,2,3,6-tetrahydro-1λ⁶-thiopyran-4- 384-Cyano-1H-imidazole-2- 0.039 0.09 carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-dimethylamino- acetyl)-piperidin-4-yl]-phenyl}- 38b4-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-methylamino-acetyl)- piperidin-4-yl]-phenyl}-amide 394-{4-[(4-Cyano-1H-imidazole-2- ND ND carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidine-1- carboxylic acid (2-hydroxy-ethyl)- 404-Cyano-1H-imidazole-2- 0.16 0.25 carboxylic acid (2-cyclohex-1-enyl-4-[1-(2-methanesulfonyl- ethyl)-piperidin-4-yl]-phenyl}- 414-Cyano-1H-imidazole-2- 0.035 ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-4- carbonyl)-piperidin-4-yl]-phenyl}- 424-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-[1-(1-oxy-pyridine-3- carbonyl)-piperidin-4-yl]-phenyl}- 434-Cyano-1H-imidazole-2- ND ND carboxylic acid{2-cyclohex-1-enyl-4-[1-(pyridine-3-carbonyl)- piperidin-4-yl]-phenyl}-amide 444-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethylamino)- acetyl]-piperidin-4-yl}-phenyl)- 454-Cyano-1H-imidazole-2- ND ND carboxylic acid (2-cyclohex-1-enyl-4-{1-[2-(2-hydroxy-ethyl)-methyl- amino-acetyl]-piperidin-4-yl}- 464-Cyano-1H-imidazole-2- ND ND carboxylic acid [4-(1-acetyl-piperidin-4-yl)-2-(1,2,5,6- tetrahydro-pyridin-3-yl)-phenyl]- 47(4-{4-[(4-Cyano-1H-imidazole-2- 0.1 ND carbonyl)-amino]-3-cyclohex-1-enyl-phenyl}-piperidin-1-yl)-acetic acid trifluoroacetic acid salt 484-Cyano-1H-imidazole-2- 0.005 ND carboxylic acid (4-[1-(3-amino-3-methyl-butyryl)-piperidin-4-yl]-2- cyclohex-1-enyl-phenyl}-amide 494H-[1,2,4]-triazole-3-carboxylic ND ND acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide bis trifluoroacetic acid salt 505-Chloro-4H-[1,2,4]-triazole-3- ND ND carboxylic acid(2-cyclohex-1-enyl- 4-piperidin-4-yl-phenyl)-amide trifluoroacetic acidsalt 51a 5-Cyano-1H-imidazole-2- 0.0043 ND carboxylic acid[2-cyclohex-1-enyl- 4-(cis-2,6-dimethyl-piperidin-4-yl)- phenyl]-amidebis trifluoroacetic 51b 5-cyano-1H-imidazole-2-carboxylic ND ND acid[2-cyclohex-1-enyl-4-(trans- 2,6-dimethyl-piperidin-4-yl)- phenyl]-amidebis trifluoroacetic 52 5-Cyano-1H-imidazole-2- 0.008 ND carboxylic acid(2-cyclohex-1- enyl-4-[1-(R)-(+)-(2,3-dihydroxy-propionyl)-piperidin-4-yl]-phenyl}- 53 5-Cyano-1H-imidazole-2- ND NDcarboxylic acid [2-cyclohex-1-enyl- 4-(1-methoxy-piperidin-4-yl)-phenyl]-amide trifluoroacetic acid 54 4-Cyano-1H-imidazole-2- ND 0.9carboxylic acid [6-(4,4-dimethyl- cyclohex-1-enyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl]- 55 4-Cyano-1H-imidazole-2- 0.012 0.25carboxylic acid [1′-(2- dimethylamino-acetyl)-6-(4,4-dimethyl-cyclohex-1-enyl)- 56 4-Cyano-1H-imidazole-2- 0.039 0.5carboxylic acid [6-(4,4-dimethyl- cyclohex-1-enyl)-1′-(2-methanesulfonyl-ethyl)- 57 5-Cyano-1H-imidazole-2- ND ND carboxylic acid(4-[1-(2-amino-2- methyl-propionyl)-piperidin-4-yl]-2-cyclohex-1-enyl-phenyl}-amide 58 5-Cyano-1H-imidazole-2- ND 1carboxylic acid [6-cyclohex-1-enyl- 1′-(2-methanesulfonyl-ethyl)-1′,2′,3′,4′,5′,6′-hexahydro-

Methods of Treatment/Prevention

The present invention comprises the use of the compounds of the presentinvention to inhibit C-KIT kinase activity in a cell or a subject, or totreat disorders related to C-KIT kinase activity or expression in asubject.

In one embodiment to this aspect, the present invention provides amethod for reducing or inhibiting the kinase activity of C-KIT in a cellcomprising the step of contacting the cell with a compound of thepresent invention. The present invention also provides a method forreducing or inhibiting the kinase activity of C-KIT in a subjectcomprising the step of administering a compound of the present inventionto the subject. The present invention further provides a method ofinhibiting cell proliferation in a cell comprising the step ofcontacting the cell with a compound of the present invention.

The kinase activity of C-KIT in a cell or a subject can be determined byprocedures well known in the art, such as the C-KIT kinase assaydescribed herein.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “contacting” as used herein, refers to the addition of compoundto cells such that compound is taken up by the cell.

In other embodiments to this aspect, the present invention provides bothprophylactic and therapeutic methods for treating a subject at risk of(or susceptible to) developing a cell proliferative disorder or adisorder related to C-KIT.

In one example, the invention provides methods for preventing in asubject a cell proliferative disorder or a disorder related to C-KIT,comprising administering to the subject a prophylactically effectiveamount of a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.Administration of said prophylactic agent can occur prior to themanifestation of symptoms characteristic of the cell proliferativedisorder or disorder related to C-KIT, such that a disease or disorderis prevented or, alternatively, delayed in its progression.

In another example, the invention pertains to methods of treating in asubject a cell proliferative disorder or a disorder related to C-KITcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.Administration of said therapeutic agent can occur concurrently with themanifestation of symptoms characteristic of the disorder, such that saidtherapeutic agent serves as a therapy to compensate for the cellproliferative disorder or disorders related to C-KIT.

The term “prophylactically effective amount” refers to an amount ofactive compound or pharmaceutical agent that inhibits or delays in asubject the onset of a disorder as being sought by a researcher,veterinarian, medical doctor or other clinician.

The term “therapeutically effective amount” as used herein, refers to anamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a subject that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of the symptoms of the disease or disorder beingtreated.

Methods for determining therapeutically and prophylactically effectivedoses for pharmaceutical compositions comprising a compound of thepresent invention are disclosed herein and known in the art.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As used herein, the terms “disorders related to C-KIT”, or “disordersrelated to C-KIT receptor”, or “disorders related to C-KIT receptortyrosine kinase” shall include diseases associated with or implicatingC-KIT activity, for example, the overactivity of C-KIT, and conditionsthat accompany with these diseases. The term “overactivity of C-KIT”refers to either 1) C-KIT expression in cells which normally do notexpress C-KIT; 2) C-KIT expression by cells which normally do notexpress C-KIT; 3) increased C-KIT expression leading to unwanted cellproliferation; or 4) mutations leading to constitutive activation ofC-KIT. Examples of “disorders related to C-KIT” include disordersresulting from over stimulation of C-KIT due to abnormally high amountof C-KIT or mutations in C-KIT, or disorders resulting from abnormallyhigh amount of C-KIT activity due to abnormally high amount of C-KIT ormutations in C-KIT. It is known that overactivity of C-KIT has beenimplicated in the pathogenesis of a number of diseases, including thecell proliferative disorders, neoplastic disorders and cancers listedbelow.

The term “cell proliferative disorders” refers to unwanted cellproliferation of one or more subset of cells in a multicellular organismresulting in harm (i.e., discomfort or decreased life expectancy) to themulticellular organisms. Cell proliferative disorders can occur indifferent types of animals and humans. As used herein “cellproliferative disorders” include neoplastic disorders.

As used herein, a “neoplastic disorder” refers to a tumor resulting fromabnormal or uncontrolled cellular growth. Examples of neoplasticdisorders include, but are not limited to, hematopoietic disorders suchas, for instance, the myeloproliferative disorders, such asthrombocythemia, essential thrombocytosis (ET), agnogenic myeloidmetaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia(MMM), chronic idiopathic myelofibrosis (IMF), and polycythemia vera(PV), the cytopenias, and pre-malignant myelodysplastic syndromes;cancers such as glioma cancers, lung cancers, breast cancers, colorectalcancers, prostate cancers, gastric cancers, gastrointestinal stromaltumors (GIST), esophageal cancers, colon cancers, pancreatic cancers,ovarian cancers, and hematoglogical malignancies, includingmyelodysplasia, multiple myeloma, leukemias and lymphomas. Examples ofhematological malignancies include, for instance, leukemias, lymphomas(non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin'slymphoma), and myeloma—for instance, acute lymphocytic leukemia (ALL),acute myeloid leukemia (AML), acute promyelocytic leukemia (APL),chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML),chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia(AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia(PML), juvenile myelomonocyctic leukemia (JMML), adult T-cell ALL, AMLwith trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL),myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD),and multiple myeloma, (MM).

In a further embodiment to this aspect, the invention encompasses acombination therapy for treating or inhibiting the onset of a cellproliferative disorder or a disorder related to C-KIT in a subject. Thecombination therapy comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofthe present invention, and one or more other anti-cell proliferationtherapy including chemotherapy, radiation therapy, gene therapy andimmunotherapy.

In an embodiment of the present invention, a compound of the presentinvention may be administered in combination with chemotherapy. As usedherein, chemotherapy refers to a therapy involving a chemotherapeuticagent. A variety of chemotherapeutic agents may be used in the combinedtreatment methods disclosed herein. Chemotherapeutic agents contemplatedas exemplary, include, but are not limited to: platinum compounds (e.g.,cisplatin, carboplatin, oxaliplatin); taxane compounds (e.g.,paclitaxcel, docetaxol); campotothecin compounds (irinotecan,topotecan); vinca alkaloids (e.g., vincristine, vinblastine,vinorelbine); anti-tumor nucleoside derivatives (e.g., 5-fluorouracil,leucovorin, gemcitabine, capecitabine); alkylating agents (e.g.,cyclophosphamide, carmustine, lomustine, thiotepa);epipodophyllotoxins/podophyllotoxins (e.g. etoposide, teniposide);aromatase inhibitors (e.g., anastrozole, letrozole, exemestane);anti-estrogen compounds (e.g., tamoxifen, fulvestrant), antifolates(e.g., premetrexed disodium); hypomethylating agents (e.g.,azacitidine); biologics (e.g., gemtuzamab, cetuximab, rituximab,pertuzumab, trastuzumab, bevacizumab, erlotinib);antibiotics/anthracyclines (e.g. idarubicin, actinomycin D, bleomycin,daunorubicin, doxorubicin, mitomycin C, dactinomycin, caminomycin,daunomycin); antimetabolites (e.g., aminopterin, clofarabine, cytosinearabinoside, methotrexate); tubulin-binding agents (e.g. combretastatin,colchicine, nocodazole); topoisomerase inhibitors (e.g., camptothecin).Further useful agents include verapamil, a calcium antagonist found tobe useful in combination with antineoplastic agents to establishchemosensitivity in tumor cells resistant to accepted chemotherapeuticagents and to potentiate the efficacy of such compounds indrug-sensitive malignancies. See Simpson W G, The calcium channelblocker verapamil and cancer chemotherapy. Cell Calcium. 1985 December;6(6):449-67. Additionally, yet to emerge chemotherapeutic agents arecontemplated as being useful in combination with a compound of thepresent invention.

In another embodiment of the present invention, the compounds of thepresent invention may be administered in combination with radiationtherapy. As used herein, “radiation therapy” refers to a therapy thatcomprises exposing the subject in need thereof to radiation. Suchtherapy is known to those skilled in the art. The appropriate scheme ofradiation therapy will be similar to those already employed in clinicaltherapies wherein the radiation therapy is used alone or in combinationwith other chemotherapeutics.

In another embodiment of the present invention, the compounds of thepresent invention may be administered in combination with a genetherapy. As used herein, “gene therapy” refers to a therapy targeting onparticular genes involved in tumor development. Possible gene therapystrategies include the restoration of defective cancer-inhibitory genes,cell transduction or transfection with antisense DNA corresponding togenes coding for growth factors and their receptors, RNA-basedstrategies such as ribozymes, RNA decoys, antisense messenger RNAs andsmall interfering RNA (siRNA) molecules and the so-called ‘suicidegenes’.

In other embodiments of this invention, the compounds of the presentinvention may be administered in combination with an immunotherapy. Asused herein, “immunotherapy” refers to a therapy targeting particularprotein involved in tumor development via antibodies specific to suchprotein. For example, monoclonal antibodies against vascular endothelialgrowth factor have been used in treating cancers.

Where a second pharmaceutical is used in addition to a compound of thepresent invention, the two pharmaceuticals may be administeredsimultaneously (e.g. in separate or unitary compositions) sequentiallyin either order, at approximately the same time, or on separate dosingschedules. In the latter case, the two compounds will be administeredwithin a period and in an amount and manner that is sufficient to ensurethat an advantageous or synergistic effect is achieved. It will beappreciated that the preferred method and order of administration andthe respective dosage amounts and regimes for each component of thecombination will depend on the particular chemotherapeutic agent beingadministered in conjunction with the compound of the present invention,their route of administration, the particular tumor being treated andthe particular host being treated.

As will be understood by those of ordinary skill in the art, theappropriate doses of chemotherapeutic agents will be generally similarto or less than those already employed in clinical therapies wherein thechemotherapeutics are administered alone or in combination with otherchemotherapeutics.

The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

By way of example only, platinum compounds are advantageouslyadministered in a dosage of 1 to 500 mg per square meter (mg/m²) of bodysurface area, for example 50 to 400 mg/m², particularly for cisplatin ina dosage of about 75 mg/m² and for carboplatin in about 300 mg/m² percourse of treatment. Cisplatin is not absorbed orally and must thereforebe delivered via injection intravenously, subcutaneously, intratumorallyor intraperitoneally.

By way of example only, taxane compounds are advantageously administeredin a dosage of 50 to 400 mg per square meter (mg/m²) of body surfacearea, for example 75 to 250 mg/m², particularly for paclitaxel in adosage of about 175 to 250 mg/m² and for docetaxel in about 75 to 150mg/m² per course of treatment.

By way of example only, camptothecin compounds are advantageouslyadministered in a dosage of 0.1 to 400 mg per square meter (mg/m²) ofbody surface area, for example 1 to 300 mg/m², particularly foririnotecan in a dosage of about 100 to 350 mg/m² and for topotecan inabout 1 to 2 mg/m² per course of treatment.

By way of example only, vinca alkaloids may be advantageouslyadministered in a dosage of 2 to 30 mg per square meter (mg/m²) of bodysurface area, particularly for vinblastine in a dosage of about 3 to 12mg/m², for vincristine in a dosage of about 1 to 2 mg/m², and forvinorelbine in dosage of about 10 to 30 mg/m² per course of treatment.

By way of example only, anti-tumor nucleoside derivatives may beadvantageously administered in a dosage of 200 to 2500 mg per squaremeter (mg/m²) of body surface area, for example 700 to 1500 mg/m².5-fluorouracil (5-FU) is commonly used via intravenous administrationwith doses ranging from 200 to 500 mg/m² (preferably from 3 to 15mg/kg/day). Gemcitabine is advantageously administered in a dosage ofabout 800 to 1200 mg/m² and capecitabine is advantageously administeredin about 1000 to 2500 mg/m² per course of treatment.

By way of example only, alkylating agents may be advantageouslyadministered in a dosage of 100 to 500 mg per square meter (mg/m²) ofbody surface area, for example 120 to 200 mg/m², particularly forcyclophosphamide in a dosage of about 100 to 500 mg/m², for chlorambucilin a dosage of about 0.1 to 0.2 mg/kg of body weight, for carmustine ina dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

By way of example only, podophyllotoxin derivatives may beadvantageously administered in a dosage of 30 to 300 mg per square meter(mg/m2) of body surface area, for example 50 to 250 mg/m², particularlyfor etoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

By way of example only, anthracycline derivatives may be advantageouslyadministered in a dosage of 10 to 75 mg per square meter (mg/m²) of bodysurface area, for example 15 to 60 mg/m², particularly for doxorubicinin a dosage of about 40 to 75 mg/m², for daunorubicin in a dosage ofabout 25 to 45 mg/m², and for idarubicin in a dosage of about 10 to 15mg/m² per course of treatment.

By way of example only, anti-estrogen compounds may be advantageouslyadministered in a dosage of about 1 to 100 mg daily depending on theparticular agent and the condition being treated. Tamoxifen isadvantageously administered orally in a dosage of 5 to 50 mg, preferably10 to 20 mg twice a day, continuing the therapy for sufficient time toachieve and maintain a therapeutic effect. Toremifene is advantageouslyadministered orally in a dosage of about 60 mg once a day, continuingthe therapy for sufficient time to achieve and maintain a therapeuticeffect. Anastrozole is advantageously administered orally in a dosage ofabout 1 mg once a day. Droloxifene is advantageously administered orallyin a dosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

By way of example only, biologics may be advantageously administered ina dosage of about 1 to 5 mg per square meter (mg/m²) of body surfacearea, or as known in the art, if different. For example, trastuzumab isadvantageously administered in a dosage of 1 to 5 mg/m² particularly 2to 4 mg/m² per course of treatment.

Dosages may be administered, for example once, twice or more per courseof treatment, which may be repeated for example every 7, 14, 21 or 28days.

The compounds of the present invention can be administered to a subjectsystemically, for example, intravenously, orally, subcutaneously,intramuscular, intradermal, or parenterally. The compounds of thepresent invention can also be administered to a subject locally.Non-limiting examples of local delivery systems include the use ofintraluminal medical devices that include intravascular drug deliverycatheters, wires, pharmacological stents and endoluminal paving. Acompound of the present invention can further be administered to asubject in combination with a targeting agent to achieve high localconcentration of a compound at the target site. In addition, thecompounds of the present invention may be formulated for fast-release orslow-release with the objective of maintaining the drugs or agents incontact with target tissues for a period ranging from hours to weeks.

The present invention also provides a pharmaceutical compositioncomprising a compound of the present invention in association with apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 0.1 mg and 1000 mg, preferably about 100 to 500mg, of the compound, and may be constituted into any form suitable forthe mode of administration selected.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, or a human, asappropriate. Veterinary uses are equally included within the inventionand “pharmaceutically acceptable” formulations include formulations forboth clinical and/or veterinary use.

Carriers include necessary and inert pharmaceutical excipients,including, but not limited to, binders, suspending agents, lubricants,flavorants, sweeteners, preservatives, dyes, and coatings. Compositionssuitable for oral administration include solid forms, such as pills,tablets, caplets, capsules (each including immediate release, timedrelease and sustained release formulations), granules, and powders, andliquid forms, such as solutions, syrups, elixirs, emulsions, andsuspensions. Forms useful for parenteral administration include sterilesolutions, emulsions and suspensions.

The pharmaceutical compositions of the present invention also include apharmaceutical composition for slow release of the compounds of thepresent invention. The composition includes a slow release carrier(typically, a polymeric carrier) and a compound of the presentinvention.

Slow release biodegradable carriers are well known in the art. These arematerials that may form particles that capture therein an activecompound(s) and slowly degrade/dissolve under a suitable environment(e.g., aqueous, acidic, basic, etc) and thereby degrade/dissolve in bodyfluids and release the active compound(s) therein. The particles arepreferably nanoparticles (i.e., in the range of about 1 to 500 nm indiameter, preferably about 50-200 nm in diameter, and most preferablyabout 100 nm in diameter).

The present invention also provides methods to prepare thepharmaceutical compositions of the invention. A compound of the presentinvention, as the active ingredient, is intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral or parenteral such as intramuscular. In preparing the compositionsin oral dosage form, any of the usual pharmaceutical media may beemployed. Thus, for liquid oral preparations, such as for example,suspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like; for solid oral preparations such as, forexample, powders, capsules, caplets, gelcaps and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Becauseof their ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. If desired, tablets may be sugar coatedor enteric coated by standard techniques. For parenterals, the carrierwill usually comprise sterile water, though other ingredients, forexample, for purposes such as aiding solubility or for preservation, maybe included. Injectable suspensions may also be prepared, in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In preparation for slow release, a slow release carrier,typically a polymeric carrier, and a compound of the present inventionare first dissolved or dispersed in an organic solvent. The obtainedorganic solution is then added into an aqueous solution to obtain anoil-in-water-type emulsion. Preferably, the aqueous solution includessurface-active agent(s). Subsequently, the organic solvent is evaporatedfrom the oil-in-water-type emulsion to obtain a colloidal suspension ofparticles containing the slow release carrier and the compound of thepresent invention.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful and the like, anamount of the active ingredient necessary to deliver an effective doseas described above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, from about 0.01 mg to 200 mg/kgof body weight per day. Preferably, the range is from about 0.03 toabout 100 mg/kg of body weight per day, most preferably, from about 0.05to about 10 mg/kg of body weight per day. The compound may beadministered on a regimen of 1 to 5 times per day. The dosages, however,may be varied depending upon the requirement of the patients, theseverity of the condition being treated and the compound(s) beingemployed. The use of either daily administration or post-periodic dosingmay be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, sterile parenteral solutions orsuspensions, metered aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories; for oral parenteral, intranasal,sublingual or rectal administration, or for administration by inhalationor insufflation. Alternatively, the composition may be presented in aform suitable for once-weekly or once-monthly administration; forexample, an insoluble salt of the active compound, such as the decanoatesalt, may be adapted to provide a depot preparation for intramuscularinjection. For preparing solid compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 0.1to about 500 mg of the active ingredient of the present invention. Thetablets or pills of the composition of the present invention can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, acetyl alcohol andcellulose acetate.

The liquid forms in which a compound of the present invention may beincorporated for administration orally or by injection include, aqueoussolutions, suitably flavored syrups, aqueous or oil suspensions, andflavored emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions, include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Advantageously, the compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds of the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The daily dosage of the products of the present invention may be variedover a wide range from 1 to 5000 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing, 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. An effective amount of a compound of the presentinvention is ordinarily supplied at a dosage level of from about 0.01mg/kg to about 200 mg/kg of body weight per day. Particularly, the rangeis from about 0.03 to about 15 mg/kg of body weight per day, and moreparticularly, from about 0.05 to about 10 mg/kg of body weight per day.The compounds of the present invention may be administered on a regimenup to four or more times per day, preferably of 1 to 2 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of lipids, including but not limited toamphipathic lipids such as phosphatidylcholines, sphingomyelins,phosphatidylethanolamines, phophatidylcholines, cardiolipins,phosphatidylserines, phosphatidylglycerols, phosphatidic acids,phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

Another alternative method for administering the compounds of theinvention may be by conjugating a compound to a targeting agent whichdirects the conjugate to its intended site of action, i.e., to vascularendothelial cells, or to tumor cells. Both antibody and non-antibodytargeting agents may be used. Because of the specific interactionbetween the targeting agent and its corresponding binding partner, thecompound of the present invention can be administered with high localconcentrations at or near a target site and thus treats the disorder atthe target site more effectively.

The antibody targeting agents include antibodies or antigen-bindingfragments thereof, that bind to a targetable or accessible component ofa tumor cell, tumor vasculature, or tumor stroma. The “targetable oraccessible component” of a tumor cell, tumor vasculature or tumorstroma, is preferably a surface-expressed, surface-accessible orsurface-localized component. The antibody targeting agents also includeantibodies or antigen-binding fragments thereof, that bind to anintracellular component that is released from a necrotic tumor cell.Preferably such antibodies are monoclonal antibodies, or antigen-bindingfragments thereof, that bind to insoluble intracellular antigen(s)present in cells that may be induced to be permeable, or in cell ghostsof substantially all neoplastic and normal cells, but are not present oraccessible on the exterior of normal living cells of a mammal

As used herein, the term “antibody” is intended to refer broadly to anyimmunologic binding agent such as IgG, IgM, IgA, IgE, F(ab′)2, aunivalent fragment such as Fab′, Fab, Dab, as well as engineeredantibodies such as recombinant antibodies, humanized antibodies,bispecific antibodies, and the like. The antibody can be either thepolyclonal or the monoclonal, although the monoclonal is preferred.There is a very broad array of antibodies known in the art that haveimmunological specificity for the cell surface of virtually any solidtumor type (see, Summary Table on monoclonal antibodies for solid tumorsin U.S. Pat. No. 5,855,866 to Thorpe et al). Methods are known to thoseskilled in the art to produce and isolate antibodies against tumor (see,U.S. Pat. No. 5,855,866 to Thorpe et al., and U.S. Pat. No. 6,34,2219 toThorpe et al.).

Techniques for conjugating therapeutic moiety to antibodies are wellknown. (See, e.g., Amon et al., “Monoclonal Antibodies ForImmunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical Applications, Pinchera et al. (eds.), pp.475-506 (1985)). Similar techniques can also be applied to attachcompounds of the invention to non-antibody targeting agents. Thoseskilled in the art will know, or be able to determine, methods offorming conjugates with non-antibody targeting agents, such as smallmolecules, oligopeptides, polysaccharides, or other polyanioniccompounds.

Although any linking moiety that is reasonably stable in blood, can beused to link the compounds of the present invention to the targetingagent, biologically-releasable bonds and/or selectively cleavablespacers or linkers are preferred. “Biologically-releasable bonds” and“selectively cleavable spacers or linkers” still have reasonablestability in the circulation, but are releasable, cleavable orhydrolyzable only or preferentially under certain conditions, i.e.,within a certain environment, or in contact with a particular agent.Such bonds include, for example, disulfide and trisulfide bonds andacid-labile bonds, as described in U.S. Pat. Nos. 5,474,765 and5,762,918 and enzyme-sensitive bonds, including peptide bonds, esters,amides, phosphodiesters and glycosides as described in U.S. Pat. Nos.5,474,765 and 5,762,918. Such selective-release design featuresfacilitate sustained release of the compounds from the conjugates at theintended target site.

The present invention further provides a method of treating of adisorder related to C-KIT, particularly a tumor, comprisingadministering to a subject a therapeutically effective amount of acompound of the present invention conjugated to a targeting agent.

When proteins such as antibodies or growth factors, or polysaccharidesare used as targeting agents, they are preferably administered in theform of injectable compositions. The injectable antibody solution willbe administered into a vein, artery or into the spinal fluid over thecourse of from 2 minutes to about 45 minutes, preferably from 10 to 20minutes. In certain cases, intradermal and intracavitary administrationare advantageous for tumors restricted to areas close to particularregions of the skin and/or to particular body cavities. In addition,intrathecal administrations may be used for tumors located in the brain.

A therapeutically effective dose of a compound of the present inventionconjugated to a targeting agent depends on the individual, the diseasetype, the disease state, the method of administration and other clinicalvariables. The effective dosages are readily determinable using datafrom animal models, including those presented herein.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A method of treating a disorder related to C KIT selected from thegroup consisting of mast cell leukemia, sinonasal natural killer/T-celllymphoma, seminoma, dysgerminoma, thyroid carcinoma, small-cell lungcarcinoma, malignant melanoma, adenoid cystic carcinoma, angiosarcoma,endometrial carcinoma, and pediatric T-cell ALL comprising administeringto a subject a therapeutically effective amount of a pharmaceuticalcomposition comprising a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is phenyl orpyridyl, either of which is optionally substituted with one of chloro,fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4triazolyl, or furanyl, any of which is connected through any carbonatom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4triazolyl, or furanyl is optionally substituted by one —Cl, —CN, —NO₂,—OMe, or —CF₃, connected to any other carbon; R² is cycloalkyl,thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl,or dihydropyranyl, any of which is optionally independently substitutedwith one or two chloro, fluoro, or C₍₁₋₃₎alkyl, with the proviso thattetrahydropyridyl is connected to the ring A through a carbon-carbonbond; X is

Z is CH or N; D¹ and D² are each hydrogen or taken together form adouble bond to an oxygen; D³ and D⁴ are each hydrogen or taken togetherform a double bond to an oxygen; D⁵ is hydrogen or —CH₃, wherein said—CH₃ is relatively oriented syn or anti; R_(a) and R_(b) are eachindependently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; E is N, S, O, SO or SO₂, with the provisothat E is not N if the following three conditions are simultaneouslymet: Q_(a) is absent, Q_(b) is absent, and R³ is an amino group orcyclic amino radical wherein the point of attachment to E is N; Q_(a) isabsent, —CH₂—, —CH₂CH₂—, or C(O); Q_(b) is absent, —NH—, —CH₂—,—CH₂CH₂—, or C(O), with the proviso that Q_(b) is not C(O) if Q_(a) isC(O), and further provided that Q_(b) is not —NH— if E is N and Q_(a) isabsent, further provided that Q_(b) is not —NH— if R³ is an amino groupor cyclic amino radical wherein the point of attachment to Q_(b) is N;R³ hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, —COOH,—CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered ring whichcontains at least one heteroatom N and optionally contains an additionalheteromoiety selected from S, SO₂, N, and O, and the 5 or 6 memberedring is optionally saturated, partially unsaturated or aromatic, whereinaromatic nitrogen in the 5 or 6 membered ring is optionally present asN-oxide, and the 5 or 6 membered ring is optionally substituted withmethyl, halogen, alkylamino, or alkoxy; or R³ is absent, with theproviso that R³ is not absent when E is nitrogen; R⁴ is hydrogen, —OH,alkoxy, carboxy, carboxamido, or carbamoyl.
 2. The method of claim 1,wherein A is phenyl or pyridyl; X is

and is oriented para with respect to —NHCO—W.
 3. The method of claim 2wherein W is 3H-2-imidazolyl-4-carbonitrile.
 4. The method of claim 3wherein R² is cyclohexenyl which is optionally substituted with one ortwo methyl groups.
 5. The method of claim 4 wherein: X is

Z is CH; D¹ and D² are each hydrogen; D³ and D⁴ are each hydrogen; D⁵ is—CH₃, wherein said —CH₃ is relatively oriented syn or anti; E is N;Q_(b) is absent, —CH₂—, —CH₂CH₂—, or C(O), with the proviso that Q_(b)is not C(O) if Q_(a) is C(O), further provided that Q_(b) is not —NH— ifR³ is an amino group or cyclic amino radical wherein the point ofattachment to Q_(b) is N; and R³ is hydrogen, hydroxyalkylamino,(hydroxyalkyl)₂-amino, alkylamino, aminoalkyl, dihydroxyalkyl, alkoxy,dialkylamino, hydroxyalkyl, —COOH, —CONH₂, —CN, —SO₂—CH₃, —NH₂, pyridyl,pyridyl-N-oxide, or morpholinyl.
 6. The method of claim 5 wherein: X is


7. The method of claim 6, further comprising administration of achemotherapeutic agent.
 8. The method of claim 6, further comprisingadministration of gene therapy.
 9. The method of claim 6, furthercomprising administration of immunotherapy.
 10. The method of claim 6,further comprising administration of radiation therapy.
 11. A method forinhibiting or reducing kinase activity of C-KIT in a cell comprisingcontacting the cell with a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: A is phenyl orpyridyl, either of which is optionally substituted with one of chloro,fluoro, methyl, —N₃, —NH₂, —NH(alkyl), —N(alkyl)₂, —S(alkyl), —O(alkyl),or 4-aminophenyl; W is pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4triazolyl, or furanyl, any of which is connected through any carbonatom, wherein the pyrrolyl, imidazolyl, isoxazolyl, oxazolyl, 1,2,4triazolyl, or furanyl is optionally substituted by one —Cl, —CN, —NO₂,—OMe, or —CF₃, connected to any other carbon; R² is cycloalkyl,thiophenyl, dihydrosulfonopyranyl, phenyl, furanyl, tetrahydropyridyl,or dihydropyranyl, any of which is optionally independently substitutedwith one or two chloro, fluoro, or C₍₁₋₃₎alkyl, with the proviso thattetrahydropyridyl is connected to the ring A through a carbon-carbonbond; X is

Z is CH or N; D¹ and D² are each hydrogen or taken together form adouble bond to an oxygen; D³ and D⁴ are each hydrogen or taken togetherform a double bond to an oxygen; D⁵ is hydrogen or —CH₃, wherein said—CH₃ is relatively oriented syn or anti; R_(a) and R_(b) areindependently hydrogen, cycloalkyl, haloalkyl, aryl, aralkyl,heteroaryl, or heteroaralkyl; E is N, S, O, SO or SO₂, with the provisothat E is N if the following three conditions are simultaneously met:Q_(a) is absent, Q_(b) is absent, and R³ is an amino group or cyclicamino radical wherein the point of attachment to E is N; Q_(a) isabsent, —CH₂—, —CH₂CH₂—, or C(O); Q_(b) is absent, —NH—, —CH₂—,—CH₂CH₂—, or C(O), with the proviso that Q_(b) is not C(O) if Q_(a) isC(O), and further provided that Q_(b) is not —NH— if E is N and Q_(a) isabsent, further provided that Q_(b) is not —NH— if R³ is an amino groupor cyclic amino radical wherein the point of attachment to Q_(b) is N;R³ is hydrogen, hydroxyalkylamino, (hydroxyalkyl)₂-amino, alkylamino,aminoalkyl, dihydroxyalkyl, alkoxy, dialkylamino, hydroxyalkyl, —COOH,—CONH₂, —CN, —SO₂-alkyl-R⁴, —NH₂, or a 5 or six membered ring whichcontains at least one heteroatom N and optionally contains an additionalheteromoiety selected from S, SO₂, N, and O, and the 5 or 6 memberedring is optionally saturated, partially unsaturated or aromatic, whereinaromatic nitrogen in the 5 or 6 membered ring is optionally present asN-oxide, and the 5 or 6 membered ring is optionally substituted withmethyl, halogen, alkylamino, or alkoxy; or R³ is absent, with theproviso that R³ is not absent when E is nitrogen; R⁴ is hydrogen, —OH,alkoxy, carboxy, carboxamido, or carbamoyl.
 12. (canceled)
 13. Themethod of claim 11, wherein the kinase activity of C-KIT in a cell isinhibited.
 14. The method of claim 11, wherein the kinase activity ofC-KIT in a cell is reduced.
 15. (canceled)
 16. The method of claim 11,wherein reduction of kinase activity of C-KIT in a cell comprisescontacting the cell with the compound:

or a pharmaceutically acceptable salt thereof.
 17. The method of claim11, wherein the inhibition of kinase activity of C-KIT in a cellcomprises contacting the cell with the compound:

or a pharmaceutically acceptable salt thereof.
 18. A method forinhibiting or reducing kinase activity of C-KIT in a subject comprisingadministering to the subject a compound of formula

or a pharmaceutically acceptable salt thereof.
 19. (canceled) 20.(canceled)
 21. The method of claim 1, wherein the compound of formula Iis a compound of formula

or a pharmaceutically acceptable salt thereof.
 22. The method of claim21, further comprising administration of a chemotherapeutic agent. 23.The method of claim 21, further comprising administration of genetherapy.
 24. The method of claim 21, further comprising administrationof immunotherapy.
 25. The method of claim 21, further comprisingadministration of radiation therapy.
 26. A method for the treatment of acell proliferative disorder selected from the group consisting of mastcell leukemia, sinonasal natural killer/T-cell lymphoma, seminoma,dysgerminoma, thyroid carcinoma, small-cell lung carcinoma, malignantmelanoma, adenoid cystic carcinoma, angiosarcoma, endometrial carcinoma,and pediatric T-cell ALL comprising administering to a subject acompound of the present invention:

or a pharmaceutically acceptable salt thereof.
 27. The method of claim26, wherein the therapeutically effective amount of the compound offormula I is administered by controlled delivery by release from anintraluminal medical device.
 28. The method of claim 27, wherein saidintraluminal medical device comprises a stent.
 29. (canceled)
 30. Themethod of claim 26, wherein the compound of formula I is conjugated to atargeting agent.
 31. (canceled)
 32. The method of claim 18, wherein thekinase activity of C-KIT in a cell is inhibited.
 33. The method of claim18, wherein the kinase activity of C-KIT in a cell is reduced.
 34. Themethod of claim 1, wherein the therapeutically effective amount of thecompound of formula I is administered by controlled delivery by releasefrom an intraluminal medical device.
 35. The method of claim 34, whereinsaid intraluminal medical device comprises a stent.
 36. The method ofclaim 1, wherein the compound of formula I is conjugated to a targetingagent.